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Review

Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy

by
Zhujiang Dai
1,2,†,
Jihong Fu
1,2,†,
Xiang Peng
1,2,
Dong Tang
3,* and
Jinglue Song
1,2,*
1
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
2
Shanghai Colorectal Cancer Research Center, Shanghai 200092, China
3
Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(19), 4796; https://doi.org/10.3390/cancers14194796
Submission received: 24 August 2022 / Revised: 27 September 2022 / Accepted: 28 September 2022 / Published: 30 September 2022
(This article belongs to the Topic Individualized Molecular Mechanisms and Treatment in Tumor Metastasis)
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Abstract

:

Simple Summary

Despite the great achievements of cancer immunotherapy in a variety of tumors, tumor heterogeneity and drug resistance still plague patients and clinical researchers. In particular, the occurrence of immune-related adverse events forces patients to discontinue cancer immunotherapy. Therefore, it is urgent to optimize cancer immunotherapy and improve the efficacy of immunotherapy. With the iteration of sequencing technology, the microbiome, as the second set of genomes in the body, has been proven to be involved in immunity and metabolism. More and more studies are gradually shifting the perspective to the intestinal microbiota and cancer immunotherapy. The intestinal microbiota reactivates and modulates immune cells in immunotherapy and is expected to become a biomarker for predicting immune efficacy. Targeting to improve the intestinal microbiota can enhance anti-tumor immunity. This advantage is beneficial to control related adverse symptoms and expand the beneficiary population of cancer immunotherapy. This finding can help clinicians comprehensively evaluate the effect of tumor screening and tumor treatment. Therefore, the innovative combination of gut microbiota and cancer immunotherapy is expected to be an active strategy to enhance individualized immune responses.

Abstract

In recent years, cancer immunotherapy has become a breakthrough method to solve solid tumors. It uses immune checkpoint inhibitors to interfere with tumor immune escape to coordinate anti-tumor therapy. However, immunotherapy has an individualized response rate. Moreover, immune-related adverse events and drug resistance are still urgent issues that need to be resolved, which may be attributed to the immune imbalance caused by immune checkpoint inhibitors. Microbiome research has fully revealed the metabolic-immune interaction relationship between the microbiome and the host. Surprisingly, sequencing technology further proved that intestinal microbiota could effectively intervene in tumor immunotherapy and reduce the incidence of adverse events. Therefore, cancer immunotherapy under the intervention of intestinal microbiota has innovatively broadened the anti-tumor landscape and is expected to become an active strategy to enhance individualized responses.

1. Introduction

Currently, immunotherapy is considered one of the most cutting-edge technological revolutions in the field of clinical oncology. Immune checkpoint inhibitors (ICIs) (such as anti-programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1), anti-cytotoxic T lymphocyte antigen 4 (CTLA-4)) indirectly exert active and effective anti-tumor immunity by inducing suppressed T cell activation [1]. Based on a large amount of clinical and medical evidence, some ICIs have been approved by the drug regulatory agency for trials or treatments of various malignant tumors [2]. However, most patients still cannot fully benefit from ICIs, which are often accompanied by primary drug resistance or immune-related adverse events [3].
In order to improve the titer of immunotherapy, actively seeking to serve biomarkers for ICIs response and toxicity prediction has become an urgent barrier to be resolved. The iterative update of sequencing technology has opened up an emerging situation in immunotherapy research [4]. The rise of metagenomics and bioinformatics has provided a new perspective on the development of microbiology in tumorigenesis [5,6]. Additionally, more and more evidence supports the important position of the microbiome in the immune-metabolic interaction of cancer, especially in response to blocking immune checkpoints [7,8,9]. This article reviews the promising future of the gut microbiota in cancer immunotherapy, including fecal microbial transplantation (FMT), probiotics, and prebiotic preparations. The intestinal microbiota is expected to provide assistance in opening up a new pattern of anti-tumor immunotherapy.

2. The Amazing Therapeutic Potential of Cancer Immunotherapy

Reports about ICIs making breakthrough progress in the field of tumor treatment are increasing day by day. Currently, the most widely used ICIs in clinical trials include anti-PD-1/PD-L1 (nivolumab/pembrolizumab/durvalumab/atezolizumab) and anti-CTLA-4 (ipilimumab) [10]. The Topalian team found that nivolumab combines clinical efficacy and high safety in the treatment of various solid tumors such as melanoma [11]. The results showed that patients with advanced melanoma without BRAF mutations had significantly improved overall survival (OS) after receiving nivolumab treatment. Meanwhile, the results of the study were also approved by another phase III randomized double-blind trial [12]. In addition, Takamida et al. reviewed the efficacy of the first-line regimen containing pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score (TPS) ≥ 50%) in the past three years [13]. The study clarified that the first-line pembrolizumab single-agent regimen significantly prolonged the patient’s OS and progression-free survival (PFS). Additionally, in the case of similar TPS, pembrolizumab combined with chemotherapy and monotherapy was beneficial to the survival of NSCLC patients [14]. However, another randomized controlled phase 3 trial comparing pembrolizumab with locally advanced NSCLC chemotherapy (KEYNOTE-042) revealed that the OS of the pembrolizumab group was significantly longer than that of the chemotherapy group (p = 0.0018) [15]. Therefore, the important position of pembrolizumab as the first-line standard therapy to treat NSCLC with high PD-L1 expression was affirmed.
Colorectal cancer (CRC) is a highly heterogeneous tumor, and its different subtypes have differentiated responses to immunotherapy [16]. CRC with high microsatellite instability (MSI-H) has high tumor mutational burden (TMB), TH1 immune infiltration, and immune checkpoint gene expression, which would have a positive effect on immunotherapy [17,18]. In MSI-H CRC, higher TMB is the objective reaction of pembrolizumab immunotherapy and the strongest biomarker of PFS [19]. However, this part of the patient accounts for 5% of the transfer of CRC patients. Microsatellite stabilization (MSS) accounts for 95% of patients with metastasis CRC and is resistant to immunotherapy [20]. High TMB MSS CRC patients have reactions to PD-1 inhibitors [21]. In addition, a prospective clinical trial (Keynote-158) found that the high TMB (TMB > 10) can effectively predict the efficacy and prognosis of Pembrolizumab [22]. This phenomenon suggests that high TMB may be used as an indicator of MSS CRC, which is conducive to the patient obtaining immunotherapy benefits. We briefly summarize the application and effect of some ICIS in solid tumors for reference (Table 1).
Currently, multiple groups of clinical trials provide evidence to support the combination of immunotherapy and chemotherapy for the treatment of a variety of malignancies. NSCLC is a pioneer in trials combining chemotherapy and immunotherapy. After observing that immunotherapy was effective in PD-L1-high (>50%) tumors and in patients treated with platinum chemotherapy, clinicians performed immunotherapy as maintenance in a phase II trial [31]. The results showed that the therapy had a significant effect on adenocarcinoma (HR 0.49; p < 0.001) and squamous cell carcinoma (HR 0.64; p < 0.001) [32]. A phase III clinical trial found that pembrolizumab combined with chemotherapy (paclitaxel/carboplatin/gemcitabine) had a significant benefit in patients with a composite positive score (CPS) ≥ 10 compared with chemotherapy alone (HR 0.65; p = 0.00411) [33]. A meta-analysis of chemotherapy combined with immunotherapy in metastatic triple-negative breast cancer (mTNBC) revealed that the addition of PD-1/PD-L1 blockade to chemotherapy improved PFS in patients with PD-L1-positive mTNBC [34]. Therefore, immunotherapy has great development space for the original tumor treatment system.

3. Combination Immunotherapy

Although ICIs show surprising therapeutic potential in tumor treatment, some patients still have difficulty benefiting from monotherapy. In order to improve the universality of immunotherapy, clinical researchers have turned their attention to combination therapy in an attempt to expand the beneficiaries of immunotherapy [35,36]. Hodi et al. evaluated a phase II randomized controlled trial of combination therapy of nivolumab and ipilimumab and monotherapy of ipilimumab for advanced melanoma [37]. Compared with ipilimumab monotherapy, the effect of combination therapy is more satisfactory [37]. Additionally, Hodi et al. added that regardless of whether BRAF is mutated or not, the first-line combination regimen or single-agent regimen can exert long-lasting clinical benefits in patients with advanced melanoma, but the combination can better improve patient survival. In order to verify whether the combination of nivolumab and ipilimumab or pembrolizumab as a chemotherapy-free first-line therapy can improve survival, Zhou et al. incorporated three randomized trials of KEYNOTE-024, KEYNOTE-042, and Checkmate 227 into the research system using the frequency method [38]. A combined meta-analysis suggested that both regimens can improve OS compared with chemotherapy (combination therapy: HR 0.82, 95% CI 0.69–0.97; monotherapy: HR 0.81, 95% CI 0.71–0.93), but only combination therapy improved PFS (combination therapy: HR 0.79, 95% CI 0.65–0.96; monotherapy: HR 1.07, 95% CI 0.94–1.21). However, combination therapy showed a higher rate of adverse events. A multicenter, retrospective cohort study on melanoma also found that combination with ipilimumab seems to have a higher objective response rate, PFS, and OS than monotherapy, but the rate of grade 3–5 toxicity is similar [39].

4. Limitations of CAR T-Cell Therapy in Solid Tumors

Chimeric antigen receptor (CAR) T cell therapy is an innovative tumor therapy that relies on cell surface antigen recombinant receptors to reactivate T lymphocytes for tumor resistance [40,41]. CAR-modified T cells not only obtain the properties of a “live drug” but also break through the constraints of traditional MHC receptors, enabling them to have long-term anti-tumor efficacy. Early clinical trials have shown that CD19 CAR-T cell therapy has a complete remission rate of up to 80% in acute lymphoblastic leukemia, significantly prolonging patient survival [42]. Notably, although transplanted T cells may be more potent than T cells from leukemia patients, it has the potential to mediate graft-versus-host disease [43]. Unfortunately, this success has not been replicated in solid tumors [44]. Solid tumors are denser in texture, have a high degree of heterogeneity in antigen expression, and are sequestered in organs or tissues. In addition, in the immunosuppressive microenvironment, it is difficult for T cell function to be at the most preferential activation level [45]. Therefore, the lack of a sufficient T cell infiltration and immunosuppressive microenvironment is the main obstacle for solid tumors to carry out CAR-T cell therapy [46]. Generally, in solid tumors, tumor-associated antigens are more accepted, such as EGFR, CEA, MUC1, etc. It is worth mentioning that these tumor-associated antigens also have lower expression in normal tissues [47,48]. Once tumor antigens lack specificity, off-target toxicity increases significantly [49,50]. For example, CRC patients treated with Her2-CAR-T cells developed severe off-target toxicity [51]. Therefore, tumor cell antigens that are differentially expressed from normal tissues must undergo rigorous evaluation and validation before they can be described as target antigens. In CRC, NKG2D, GUCY2C, and TAG-72 are promising target antigens [52,53,54]. A recent report pointed out that DCLK1-targeted CAR-T therapy has a significant effect on primary or metastatic CRC [55,56]. Surprisingly, a study indicated that bispecific Trop2/PDL1 CAR-T cells could significantly inhibit gastric cancer growth by intratumoral injection, and its inhibitory effect was more significant than that of Trop2-specific CAR-T cells [57]. In addition, CXCR2-expressing CAR-T cells were more sensitive to the IL-8-rich microenvironment in pancreatic cancer and had stronger anti-tumor activity against αvβ6-expressing pancreatic tumor xenografts [58]. Therefore, the combination of CAR-T cell therapy and ICIs seems to be more conducive to the tumor suppressor effect.

5. Immune-Related Adverse Events

With the continuous promotion of ICIs in the clinic, immune-related adverse events have shown an exponential increase, which has become a major clinical challenge [59,60]. Although immune-related adverse events are not fatal, they often force patients and bedside physicians to make a clinical decision about whether to continue treatment. According to statistics, nivolumab induces endocrine toxicity, while pembrolizumab induces liver toxicity and joint pain [61]. Ipilimumab most commonly affects the skin and gastrointestinal tract and also has partial renal toxicity. A meta-analysis of the risk of ICIs supports that combination therapy (ipilimumab/nivolumab) is more likely to induce immune-related endocrine risk than monotherapy [62]. Another analysis added that combination therapy might even lead to discontinuation with high adverse effects [63]. However, appropriate combination regimens remain the primary consideration for clinicians compared with treatment-induced mortality. So far, the treatment of immune-related adverse events has mostly followed the empirical management of autoimmune diseases. Therefore, improving the complications of immunotherapy or exploring immune checkpoints with more therapeutic advantages are innovative measures. We briefly summarize partial immune-related adverse events and organizations and organs involved to provide reference to ICIs (Figure 1). With the advancement of sequencing, it was discovered that the intestinal microbiota is deeply involved in human metabolism and immunity, including tumors. Additionally, researchers are also gradually exploring how gut microbes reverse immune-related adverse events (Table 2).

6. Intestinal Microbiota Regulates Pharmacokinetics

Pharmacokinetics refers to the laws of drug absorption, distribution, metabolism, and excretion in the body [74]. Several studies have suggested that the gut microbiota may lead to changes in the chemical modification of medicinal products, resulting in activation, inactivation, or toxicity [75]. However, quantifying microbial intervention on pharmacokinetics remains challenging, especially based on the common basis of drug metabolism of the host and microbiota. Zimmermann M’s team combined the genetics of microbial symbiosis with gnotobiotics for the first time [76]. By monitoring the metabolic changes of brivudine (BRV) in mice caused by a single microbially encoded enzyme, they innovatively established a pharmacokinetic model and predicted quantitative microbial contributions to systemic drug metabolism [76]. They compared the serum kinetics of oral BRV in conventional (CV) and germ-free (GF) mice and demonstrated that BRV is converted to hepatotoxic bromoyluracil (BVU) by microbial enzymes, reducing BVU exposure in GF mice [76]. BVU interferes with pyrimidine metabolism in humans by binding to DPD, with lethal consequences in patients receiving chemotherapy with pyrimidine-like drugs such as 5-fluorouracil (5-FU) [77]. In addition, they found that Bacteroides and Oobacteria had the highest metabolic activity to convert BRV to BVU. This study provides the microbiome’s understanding of drug metabolism and aims to improve the response to drugs in chemotherapy patients. Additionally, they mapped human microbial drug metabolism by measuring the drug-modifying capacity of representative gut bacterial generations and systematically analyzing drug–microbe interactions by identifying drug-metabolizing microbial gene products [78]. Therefore, microbial intervention has a positive strategic effect on chemotherapy and drug metabolism.

7. Microbiota Correlates with Cancer Immunotherapy

The microbiota mainly inhabits the human intestines and maintains the host’s metabolism and immune crosstalk [79]. The microbial genome is more than 150 times that of the human body itself, so it is also called the second set of the human genome [80]. It covers a cumulative total of more than 1000 bacterial species, which endows the metagenomics with a common core while maintaining individual differences. Driven by the revolution of high-throughput sequencing technology, microbial research has quickly entered a new era of whole-genome sequencing from laboratory culture [81]. Metagenomics can also be combined with other omics to analyze the metabolism and immune processes of microorganisms, including transcriptomics, metabolomics, and proteomics [82,83]. Surprisingly, the intestinal microbiota has gradually been recognized as being able to intervene effectively in tumor immunotherapy, reduce the incidence of adverse events, and benefit patients [84].
In the early stage, in order to determine whether the microbiome interferes with the therapeutic activity of ICIs, melanoma mice (TAC mice with more severe tumors) carrying different intestinal microbiota but the same genotype from TAC and JAX were used to assess their correlation [85]. The results showed that Bifidobacterium was most significantly enriched in the feces of JAX mice and had a higher correlation with peripheral and intratumoral specific CD8+ T cell activation. Interestingly, after TAC mice were further transplanted or co-cultured with JAX mouse fecal bacteria, the differences between the two gradually approached [86]. This also directly established the status of the gut microbiome in immunotherapy. In the later stage, after PD-L1 ICIs were combined with mouse fecal suspension, tumor invasion and growth were consistently and significantly slowed, as expected [85].

8. Gut Microbiome Expands Path for Cancer Immunotherapy

In addition, Chaput et al. speculated from the baseline microbiome that the incidence of colitis in patients with metastatic melanoma treated with ipilimumab is regulated by the microbiome [87]. The study prospectively proposed that identifying the attributes of the microbiota is beneficial to avoid and control adverse risks that patients may encounter [87]. According to the RECIST 1.1 standard, patients with different microbiomes can be classified as responders (R) and non-responders (NR) [88]. On this basis, Derosa et al. successfully inoculated feces from R into NR through FMT technology to compensate for the anti-PD-1 immune effect [89,90]. Although the advantages of the microbiome in immunotherapy have become increasingly prominent, there are still challenges in screening out bacterial groups that are specifically enriched for ICIs [91]. With the support of Metatagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling, stool analysis of R and NR is expected to provide clues for the identification of the intestinal microbiota [92].
Although the preclinical mouse model of intestinal microbiota intervention ICIs has been established, there is still a lack of evidence for its application to cancer patients. By analyzing the stool samples of melanoma patients treated with ICIs, Gopalakrishnan and others found significant differences in the diversity and number of intestinal microbiota between responders and non-responders [10]. In particular, the alpha diversity (a statistical method of the distribution and composition of bacteria in the sample) and the relative abundance of Ruminococcaceae (p < 0.01) in the feces of the responders were significantly increased, and the function of effector T cells in the tumor microenvironment (TME) was improved [10]. On the contrary, the feces of non-responders is often accompanied by a lower abundance of bacteria, and there is an enrichment of Bacteroidales, which block lymphatic infiltration and impair tumor immune response.
In an independent cohort study of combined treatment (ipilimumab plus nivolumab) of metastatic melanoma, Frankel et al. reported an increase in the abundance of Faecalibacterium in baseline stool samples of responders and non-responders [7]. The abundance of Faecalibacterium and the longer PFS showed a positive correlation trend [92]. According to the immunophenotype analysis of matched tumors and blood samples of patients in this cohort, the abundance of Faecalibacterium not only has a strong positive correlation with CD8 + T infiltration in the TME but also has a certain correlation with peripheral CD4+/CD8 + T cells [92]. Furthermore, in 32 NSCLC patients, enrichment of Enterococcus faecium also enhanced peripheral CD8+/CD4 + T cell responses and IFN-γ production, prolonging the PFS of R [93].
Coincidentally, by analyzing the stool samples from patients with metastatic melanoma, Matson et al. found that the degree of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium enrichment in patients with anti-PD-1 was positively correlated with treatment response and inhibited tumor growth [94]. Additionally, after FMT rebuilds the intestinal environment of sterile mice, tumor control is significantly strengthened. This increased therapeutic effect is mediated by the activation of DCs, which leads to increased initiation and accumulation of CD8 + T cells in TME [95]. This also verifies that the intestinal microbiota from responders is involved in improving immunotherapy or as a candidate biomarker to promote immune surveillance of cancer [96]. Through 16S ribosomal RNA sequencing identification, Sivan et al. found that the effect of oral Bifidobacterium alone can be comparable to anti-PD-1 therapy, and the combined therapy can even completely inhibit tumors [85]. In addition, the metabolites of the microbiota not only reactivate dendritic cells (DCs) but also induce the metabolic reorganization of CD8 + T cells in the TME, providing a basis for the long-term survival of memory cells [97].
When comparing the intestinal microbiota of patients with different malignancies receiving immunotherapy, Routy et al. found that Akkermansia muciniphila (A. muciniphila) was more enriched in the feces of responders (p = 0.007) [90]. Interestingly, two independent teams studying NSCLC and renal cell carcinoma and studying metastatic melanoma also reached similar conclusions, suggesting the possibility of A. muciniphila as a biomarker [98,99]. It is worth mentioning that after co-culture of A. muciniphila with peripheral blood mononuclear cells of responders or non-responders, the effect of responders’ CD4+/CD8 + T cells in producing IFN-γ-related memory T cells was significantly stronger than that of non-responders [100]. At the same time, passing A. muciniphila through FMT can re-establish the immune checkpoint blocking effect of non-responders.
In addition, Bacteroidetes are increasingly recognized to be associated with the development and exacerbation of induced colitis [101,102]. In melanoma patients treated with ICIs, the abundance of Bacteroidetes appears to be positively correlated with colitis resistance [103]. Recently, a number of studies proved that different microbial populations excel in optimizing the therapeutic effects of different ICIs, improving the prognosis of patients [104,105]. We summarized the microbiota, tumors, and related immune regulation mechanisms involved in each study in Table 3.
In short, these studies broaden the perspective of the intestinal microbiota participating in cancer immunotherapy [106]. In fact, a variety of factors, such as diet, daily life, and drugs, are the basis for constructing the network of immune metabolism of the intestinal microbiota. Therefore, different life parameters may also affect the responsiveness of the intestinal microbiota in different populations and tumors.
Table
Table 3. Intestinal microbiota optimizes cancer immunotherapy.
Table 3. Intestinal microbiota optimizes cancer immunotherapy.
Microbial SpeciesImmune OptimizationAnti-PD-1/L1Anti-CTLA-4TumorsReferences
Alistipes putredinisMemory CD8+ T cells ↑
NK cells(peripheral) ↑		↑ NSCLC
RCC		[100]
Akkermansia muciniphilaCXCR3+CCR9+CD4+ T cells ↑
DCs ↑
IL-12 ↑		↑ NSCLC
RCC		[100]
Bacteroides spp. MDSCs and Tregs ↑
Immune-related adverse events ↑
IL-12 ↓
DCs ↓		↓↓MM[87]
Bacteroides fragilisTh1 cells ↑
Foxp3+ Tregs ↑
DCs ↑		 ↑MM
NSCLC		[107]
Bifidobacterium spp. DCs ↑
Lymphocytes ↑
IFN-γ ↑
Pro-inflammatory cytokine ↑
Tumor-specific CD8+ T cells ↑		↑ MM[94]
[85]
Enterococcus faeciumT cell responses ↑↑ MM[10]
Escherichia
Clostridium		Differentiation of Tregs ↑
Inflammation ↓		 ↑MM[7]
Faecalibacterium. spp. CD4+/CD8+ T cells ↑
Tregs ↑
ICOS expression of T cells ↑		↑↑MM[87]
Ruminococcaceae spp. Antigen presentation ↑
T cells ↑
IFN-γ CD8+ T cells ↑		↓ MM[94]
Microbial-derived SCFAs
(butyrate, propionate)		Differentiation of Tregs ↑ ↑CRC[108]

9. The Clinical Application of Intestinal Microbiota

With the continuous expansion of research data, the gut microbiota provides unprecedented opportunities for the development of immunotherapy-related therapies. Although the mechanism of the gut microbiota in cancer immunotherapy remains to be explored, many cutting-edge studies provide valuable clinical evidence for the gut microbiota with application potential. According to recent clinical studies, we use a Sankey diagram to build a very meaningful bridge between ICIs (anti-PD-1/PD-L1 or anti-CTLA-4) and the enrichment of the intestinal microbiota (Figure 2).
Intestinal microbiota optimization and adjuvant immunotherapy have been confirmed, which provides confidence in reducing the complications of cancer immunotherapy [110]. Among them, the most common immune-related adverse event is related to colitis, but the cause is still unknown. Interestingly, colitis was effectively relieved under the intervention of the lactic acid bacteria Lactobacillus reuteri, and the patient’s weight loss and inflammation symptoms were significantly improved [111]. In addition, the activation of the protection of Lactobacillus reuteri may be based on the decrease in lymphocyte distribution [112]. The emergence of tumor microecological immunonutrition further provides an opportunity for the microbiota as a breakthrough in cancer immunotherapy [113]. The ketogenic diet has also been reported to enhance the efficacy of immunotherapy [114].
A number of studies have proposed that adjusting the composition of the gut microbiota can effectively improve immunotherapy, including FMT, dietary intervention, probiotics, or prebiotics [115]. Among them, FMT is gradually recognized as a beneficial clinical intervention. FMT is perfused or orally transplanted into the patient’s intestines in the form of bacterial liquid or capsules [116]. At present, FMT has been proven to be the first-line treatment for relapsed/refractory Clostridium difficile infection (CDI) and has been included in the national clinical guidelines [117]. Since microbial research turns to an in-depth mechanism direction, the role of the microbiota and metabolites in the field of inflammatory bowel disease and cancer will undoubtedly be further highlighted [118,119,120]. Certainly, FMT is in its infancy in cancer clinical exploration, but it is a landmark discovery in the field of cancer therapy.

10. The Combination of FMT and Immunotherapy

The combination therapy of FMT and ICIs not only takes into account the curative effect but also guarantees better safety. Baruch et al. performed intestinal microbiota reconstruction in 10 groups of patients with anti-PD-1 refractory metastatic melanoma [121]. After using vancomycin to destroy their own intestinal microbiota for 3 days, the patient rebuilt a new intestinal environment through FMT [122]. After receiving the anti-PD-1 ICIs again, two patients had partial remission, and one patient had complete remission with PFS for more than 6 months. Only some patients experienced discomfort, such as abdominal distension, and no other adverse reactions occurred [123].
Another study also performed FMT and PD-1 monoclonal antibody combination therapy on 15 patients with anti-PD-1 resistant metastatic melanoma [124]. The results showed that six patients responded to anti-PD-1, and only three patients experienced grade 3 adverse events. The study also further clarified that the combination of FMT and anti-PD-1 therapy weakened bone marrow-induced immune suppression, activated CD56 + CD8 + T cells, and downregulated the expression of IL-8 [125]. In contrast, patients with poor intestinal microbiota exhibited weak anti-tumor immunity due to restricted antigen presentation. The latest FMT and immunotherapy-related clinical trials provide a basis for clarifying the involvement of intestinal microbiota in the regulation of ICIs (Table 4). The clinical trial (NCT03353402) attempts to improve the gut microbiota of melanoma patients who cannot benefit from immunotherapy through FMT. Another clinical trial (NCT05008861) tried to rebuild the gut microbiota in the immunotherapy of non-small cell lung cancer through FMT. The combination of FMT and ICIs will make a greater contribution to the prognosis of patients. In addition, before the combination therapy of FMT and ICIs, the patient must consume antibiotics orally to destroy the harmful intestinal microbiota in the body. According to reports, the vancomycin–neomycin regimen is currently the most effective preparation for treatment [126]. The results of clinical trials and conventional treatment indicate that antibiotic exposure may reduce the OS rate of patients receiving immunotherapy, but the potential intervention is not yet clear [12,13].

11. Probiotics and Prebiotics

Undoubtedly, FMT is a highly potential microbial intervention therapy. However, before clinical application, pathogen screening is indispensable to prevent the induction of bacteremia. Probiotics and prebiotics have received widespread attention due to their low price and easy access [127]. As a biological response modifier, probiotics are involved in the competitive displacement of pathogens, the assembly of antiviral proteins, and the maintenance of physiological functions of the epithelial–mucosal barrier [128]. Probiotics not only directly regulate immune and metabolic processes through intestinal immune cells and epithelial cells but also indirectly maintain the immune state of multiple sites by regulating intestinal microbiota [129]. Probiotics, such as Lactobacillus and Bifidobacterium, can promote antigen-specific recognition of infected monocytes to cut off the transmission route [28,130]. A clinical trial involving 20 CRC patients (NCT03072641) revealed that bifidobacteria and lactobacilli altered the immune responsiveness of the intestinal mucosa compared with baseline tissue or stool samples [131]. Further, the clinical trial also found changes in the expression of cytokines, such as IL-10, IL-12, IL-17, etc., in the mucosa [131]. Coincidentally, probiotic preparations containing Lactobacillus casei have significantly improved in ensuring surgical resection and recurrence-free survival of bladder cancer [132]. In addition, there is evidence that prebiotics such as inulin, lactulose, and galactooligosaccharides can selectively induce the proliferation of bifidobacteria and lactobacilli [133,134]. However, due to a lack of scientifically rigorous evidence, most probiotics and prebiotics are still not included in the drug category. The initial success of probiotics in CDI and inflammatory bowel disease has given strong confidence and spurred a focus on providing strong scientific evidence for their efficacy [135]. It cannot be ignored that the fraction of the symbiotic microbiota with lower individual variability is of great significance in manipulating host physiology. Tanoue et al. obtained 11 fecal microbiota derived from healthy people and found that they strongly induced interferon γ + CD8 T cells [136]. Further colonizing the microbiota in mice, they found that the mixed microbiota not only enhanced the anti-tumor immune effect of ICIs but also effectively avoided immune-related colitis [136]. Therefore, the research on the microbiome will provide a powerful boost to the progress of clinical tumors and other multidisciplinary subjects.

12. Antibiotic and Immunotherapy Efficacy

For immunotherapy patients, the use of antibiotics should be carefully weighed. Exposure to broad-spectrum antibiotics, even when the source of infection is identified, can still impair gut microbiota homeostasis in cancer patients receiving immunotherapy [137]. One study showed that, regardless of whether antibiotics were used before and after anti-PD-1, the median survival rate of patients was only half that of those who did not receive antibiotic exposure [138]. A multicenter, prospective cohort study of 196 samples (NSCLC, melanoma, RCC, and head and neck cancer) also supported that antibiotics reduce PD-1/PD-L1 response to treatment, and patients have lower OS [139]. However, a retrospective study of 74 NSCLC patients treated with nivolumab did not find significant differences in efficacy or PFS [140]. Although the impact of antibiotics on immunotherapy remains controversial, it is undeniable that clinicians need to carefully consider the duration and dose of antibiotic exposure. We look forward to more prospective studies being conducted to clarify this issue.

13. Conclusions

The intestinal microbiota and immunotherapy are a new cross-cutting field. Microbiota association research and avant-garde sequencing technologies have shifted from descriptive macroscopic research to the regulation of the immune metabolism of specific microbiota. Through intervention modes such as FMT, the microbiota can not only reduce immune-related adverse events but also serve as a biomarker to predict the prognosis of patients. Based on clinical trials and bioinformatics data, the development of accurate and effective individualized microbial therapy will be the direction of tumor treatment in the future.

Author Contributions

Conceptualization, Z.D. and D.T.; Validation, J.F. and Z.D.; Data Curation, J.F. and X.P.; Writing—Original Draft Preparation, Z.D. and X.P.; Writing—Review and Editing, J.F., J.S. and D.T.; Visualization, Z.D.; Funding Acquisition, J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was sponsored by the National Natural Science Foundation of China (82002507) and the Shanghai Sailing Program (20YF1430100).

Conflicts of Interest

The authors declare that there is no conflict of interest.

Abbreviations

Colorectal cancer: CRC; cytotoxic T lymphocyte antigen 4: CTLA-4; dendritic cells: DCs; fecal microbial transplantation: FMT; high microsatellite instability: MSI-H; immune checkpoint inhibitors: ICIs; Microsatellite Stabilization: MSS; metastatic triple-negative breast cancer: mTNBC; non-responders: NR; non-small cell lung cancer: NSCLC; overall survival: OS; programmed death receptor 1/programmed death ligand 1: PD-1/PD-L1; progression-free survival: PFS; tumor microenvironment: TME; tumor mutation burden: TMB.

References

  1. Nakajima, H.; Nakatsura, T. Towards the era of immune checkpoint inhibitors and personalized cancer immunotherapy. Immunol. Med. 2021, 44, 10–15. [Google Scholar] [CrossRef] [PubMed]
  2. Wang, Y.; Tong, Z.; Zhang, W.; Zhang, W.; Buzdin, A.; Mu, X.; Yan, Q.; Zhao, X.; Chang, H.H.; Duhon, M.; et al. FDA-Approved and Emerging Next Generation Predictive Biomarkers for Immune Checkpoint Inhibitors in Cancer Patients. Front. Oncol. 2021, 11, 683419. [Google Scholar] [CrossRef] [PubMed]
  3. Huang, Y.; Soon, Y.Y.; Aminkeng, F.; Tay, S.H.; Ang, Y.; Kee, A.C.L.; Goh, B.C.; Wong, A.S.C.; Soo, R.A. Risk factors for immune-related adverse events from anti-PD-1 or anti-PD-L1 treatment in an Asian cohort of nonsmall cell lung cancer patients. Int. J. Cancer 2021, 150, 636–644. [Google Scholar] [CrossRef] [PubMed]
  4. Derakhshani, A.; Rostami, Z.; Safarpour, H.; Shadbad, M.A.; Nourbakhsh, N.S.; Argentiero, A.; Taefehshokr, S.; Tabrizi, N.J.; Kooshkaki, O.; Astamal, R.V.; et al. From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy. Molecules 2021, 26, 2278. [Google Scholar] [CrossRef] [PubMed]
  5. O’Sullivan, D.M.; Doyle, R.M.; Temisak, S.; Redshaw, N.; Whale, A.S.; Logan, G.; Huang, J.; Fischer, N.; Amos, G.C.A.; Preston, M.D.; et al. An inter-laboratory study to investigate the impact of the bioinformatics component on microbiome analysis using mock communities. Sci. Rep. 2021, 11, 10590. [Google Scholar] [CrossRef]
  6. Tourlousse, D.M.; Narita, K.; Miura, T.; Sakamoto, M.; Ohashi, A.; Shiina, K.; Matsuda, M.; Miura, D.; Shimamura, M.; Ohyama, Y.; et al. Validation and standardization of DNA extraction and library construction methods for metagenomics-based human fecal microbiome measurements. Microbiome 2021, 9, 95. [Google Scholar] [CrossRef]
  7. Frankel, A.E.; Deshmukh, S.; Reddy, A.; Lightcap, J.; Hayes, M.; McClellan, S.; Singh, S.; Rabideau, B.; Glover, T.G.; Roberts, B.; et al. Cancer Immune Checkpoint Inhibitor Therapy and the Gut Microbiota. Integr. Cancer 2019, 18, 1534735419846379. [Google Scholar] [CrossRef]
  8. Fessler, J.; Matson, V.; Gajewski, T.F. Exploring the emerging role of the microbiome in cancer immunotherapy. J. Immunother. Cancer 2019, 7, 108. [Google Scholar] [CrossRef]
  9. Vetizou, M.; Pitt, J.M.; Daillere, R.; Lepage, P.; Waldschmitt, N.; Flament, C.; Rusakiewicz, S.; Routy, B.; Roberti, M.P.; Duong, C.P.; et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015, 350, 1079–1084. [Google Scholar] [CrossRef]
  10. Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018, 359, 97–103. [Google Scholar] [CrossRef] [Green Version]
  11. Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454. [Google Scholar] [CrossRef] [PubMed]
  12. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef] [PubMed]
  13. Tamiya, M.; Tamiya, A.; Hosoya, K.; Taniguchi, Y.; Yokoyama, T.; Fukuda, Y.; Hirano, K.; Matsumoto, H.; Kominami, R.; Suzuki, H.; et al. Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: A multicenter retrospective cohort study (HOPE-001). Investig. New Drugs 2019, 37, 1266–1273. [Google Scholar] [CrossRef] [PubMed]
  14. Dudnik, E.; Moskovitz, M.; Rottenberg, Y.; Lobachov, A.; Mandelboim, R.; Shochat, T.; Urban, D.; Wollner, M.; Nechushtan, H.; Rotem, O.; et al. Pembrolizumab as a monotherapy or in combination with platinum-based chemotherapy in advanced non-small cell lung cancer with PD-L1 tumor proportion score (TPS) >/=50%: Real-world data. Oncoimmunology 2021, 10, 1865653. [Google Scholar] [CrossRef] [PubMed]
  15. Mok, T.S.K.; Wu, Y.L.; Kudaba, I.; Kowalski, D.M.; Cho, B.C.; Turna, H.Z.; Castro, G., Jr.; Srimuninnimit, V.; Laktionov, K.K.; Bondarenko, I.; et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 2019, 393, 1819–1830. [Google Scholar] [CrossRef]
  16. Elez, E.; Baraibar, I. Immunotherapy in colorectal cancer: An unmet need deserving of change. Lancet Oncol. 2022, 23, 830–831. [Google Scholar] [CrossRef]
  17. Lee, D.W.; Han, S.W.; Bae, J.M.; Jang, H.; Han, H.; Kim, H.; Bang, D.; Jeong, S.Y.; Park, K.J.; Kang, G.H.; et al. Tumor Mutation Burden and Prognosis in Patients with Colorectal Cancer Treated with Adjuvant Fluoropyrimidine and Oxaliplatin. Clin. Cancer Res. 2019, 25, 6141–6147. [Google Scholar] [CrossRef]
  18. Picard, E.; Verschoor, C.P.; Ma, G.W.; Pawelec, G. Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer. Front. Immunol. 2020, 11, 369. [Google Scholar] [CrossRef]
  19. Andre, T.; Amonkar, M.; Norquist, J.M.; Shiu, K.K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.J.A.; Smith, D.; Garcia-Carbonero, R.; et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): An open-label, randomised, phase 3 trial. Lancet Oncol. 2021, 22, 665–677. [Google Scholar] [CrossRef]
  20. Chen, L.; Jiang, X.; Li, Y.; Zhang, Q.; Li, Q.; Zhang, X.; Zhang, M.; Yu, Q.; Gao, D. How to overcome tumor resistance to anti-PD-1/PD-L1 therapy by immunotherapy modifying the tumor microenvironment in MSS CRC. Clin. Immunol. 2022, 237, 108962. [Google Scholar] [CrossRef]
  21. Xiao, J.; Li, W.; Huang, Y.; Huang, M.; Li, S.; Zhai, X.; Zhao, J.; Gao, C.; Xie, W.; Qin, H.; et al. A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer. BMC Cancer 2021, 21, 282. [Google Scholar] [CrossRef] [PubMed]
  22. Maio, M.; Amonkar, M.M.; Norquist, J.M.; Ascierto, P.A.; Manzyuk, L.; Motola-Kuba, D.; Penel, N.; Cassier, P.A.; Bariani, G.M.; De Jesus Acosta, A.; et al. Health-related quality of life in patients treated with pembrolizumab for microsatellite instability-high/mismatch repair-deficient advanced solid tumours: Results from the KEYNOTE-158 study. Eur. J. Cancer 2022, 169, 188–197. [Google Scholar] [CrossRef] [PubMed]
  23. Santin, A.D.; Deng, W.; Frumovitz, M.; Buza, N.; Bellone, S.; Huh, W.; Khleif, S.; Lankes, H.A.; Ratner, E.S.; O’Cearbhaill, R.E.; et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol. Oncol. 2020, 157, 161–166. [Google Scholar] [CrossRef] [PubMed]
  24. Hellmann, M.D.; Janne, P.A.; Opyrchal, M.; Hafez, N.; Raez, L.E.; Gabrilovich, D.I.; Wang, F.; Trepel, J.B.; Lee, M.J.; Yuno, A.; et al. Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy. Clin. Cancer Res. 2021, 27, 1019–1028. [Google Scholar] [CrossRef]
  25. Tewari, K.S.; Monk, B.J.; Vergote, I.; Miller, A.; de Melo, A.C.; Kim, H.S.; Kim, Y.M.; Lisyanskaya, A.; Samouelian, V.; Lorusso, D.; et al. Survival with Cemiplimab in Recurrent Cervical Cancer. N. Engl. J. Med. 2022, 386, 544–555. [Google Scholar] [CrossRef]
  26. Adams, S.; Diamond, J.R.; Hamilton, E.; Pohlmann, P.R.; Tolaney, S.M.; Chang, C.W.; Zhang, W.; Iizuka, K.; Foster, P.G.; Molinero, L.; et al. Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial. JAMA Oncol. 2019, 5, 334–342. [Google Scholar] [CrossRef]
  27. Ascierto, P.A.; Orlova, K.; Grignani, G.; Dudzisz-Sledz, M.; Fenig, E.; Chiarion Sileni, V.; Fazio, N.; Samimi, M.; Mortier, L.; Gebhardt, C.; et al. Avelumab expanded access program in metastatic Merkel cell carcinoma: Efficacy and safety findings from patients in Europe and the Middle East. Int. J. Cancer 2021, 149, 1926–1934. [Google Scholar] [CrossRef]
  28. Riudavets, M.; Auclin, E.; Mosteiro, M.; Dempsey, N.; Majem, M.; Lobefaro, R.; Lopez-Castro, R.; Bosch-Barrera, J.; Pilotto, S.; Escalera, E.; et al. Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations. Eur. J. Cancer 2022, 167, 142–148. [Google Scholar] [CrossRef]
  29. Eggermont, A.M. Adjuvant ipilimumab in stage III melanoma: New landscape, new questions. Eur. J. Cancer 2016, 69, 39–42. [Google Scholar] [CrossRef]
  30. Overman, M.J.; Lonardi, S.; Wong, K.Y.M.; Lenz, H.J.; Gelsomino, F.; Aglietta, M.; Morse, M.A.; Van Cutsem, E.; McDermott, R.; Hill, A.; et al. Durable Clinical Benefit with Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J. Clin. Oncol. 2018, 36, 773–779. [Google Scholar] [CrossRef] [PubMed]
  31. Reck, M.; Rodriguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csoszi, T.; Fulop, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2016, 375, 1823–1833. [Google Scholar] [CrossRef] [PubMed]
  32. Reck, M.; Rodriguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csoszi, T.; Fulop, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J. Clin. Oncol. 2019, 37, 537–546. [Google Scholar] [CrossRef] [PubMed]
  33. Cortes, J.; Cescon, D.W.; Rugo, H.S.; Nowecki, Z.; Im, S.A.; Yusof, M.M.; Gallardo, C.; Lipatov, O.; Barrios, C.H.; Holgado, E.; et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020, 396, 1817–1828. [Google Scholar] [CrossRef]
  34. Huo, X.; Shen, G.; Liu, Z.; Liang, Y.; Li, J.; Zhao, F.; Ren, D.; Zhao, J. Addition of immunotherapy to chemotherapy for metastatic triple-negative breast cancer: A systematic review and meta-analysis of randomized clinical trials. Crit. Rev. Oncol. Hematol. 2021, 168, 103530. [Google Scholar] [CrossRef]
  35. Huang, W.; Chen, J.J.; Xing, R.; Zeng, Y.C. Combination therapy: Future directions of immunotherapy in small cell lung cancer. Transl. Oncol. 2021, 14, 100889. [Google Scholar] [CrossRef]
  36. Kaur, J.; Elms, J.; Munn, A.L.; Good, D.; Wei, M.Q. Immunotherapy for non-small cell lung cancer (NSCLC), as a stand-alone and in combination therapy. Crit. Rev. Oncol. Hematol. 2021, 164, 103417. [Google Scholar] [CrossRef]
  37. Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018, 19, 1480–1492. [Google Scholar] [CrossRef]
  38. Zhou, Y.; Zhang, Y.; Guo, G.; Cai, X.; Yu, H.; Cai, Y.; Zhang, B.; Hong, S.; Zhang, L. Nivolumab plus ipilimumab versus pembrolizumab as chemotherapy-free, first-line treatment for PD-L1-positive non-small cell lung cancer. Clin. Transl. Med. 2020, 10, 107–115. [Google Scholar] [CrossRef]
  39. Pires da Silva, I.; Ahmed, T.; Reijers, I.L.M.; Weppler, A.M.; Betof Warner, A.; Patrinely, J.R.; Serra-Bellver, P.; Allayous, C.; Mangana, J.; Nguyen, K.; et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: A multicentre, retrospective, cohort study. Lancet Oncol. 2021, 22, 836–847. [Google Scholar] [CrossRef]
  40. Amini, L.; Silbert, S.K.; Maude, S.L.; Nastoupil, L.J.; Ramos, C.A.; Brentjens, R.J.; Sauter, C.S.; Shah, N.N.; Abou-El-Enein, M. Preparing for CAR T cell therapy: Patient selection, bridging therapies and lymphodepletion. Nat. Rev. Clin. Oncol. 2022, 19, 342–355. [Google Scholar] [CrossRef]
  41. Kankeu Fonkoua, L.A.; Sirpilla, O.; Sakemura, R.; Siegler, E.L.; Kenderian, S.S. CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities. Mol. Oncolytics 2022, 25, 69–77. [Google Scholar] [CrossRef] [PubMed]
  42. Globerson Levin, A.; Riviere, I.; Eshhar, Z.; Sadelain, M. CAR T cells: Building on the CD19 paradigm. Eur. J. Immunol. 2021, 51, 2151–2163. [Google Scholar] [CrossRef] [PubMed]
  43. Mansouri, V.; Yazdanpanah, N.; Rezaei, N. The immunologic aspects of cytokine release syndrome and graft versus host disease following CAR T cell therapy. Int. Rev. Immunol. 2021, 1–20. [Google Scholar] [CrossRef] [PubMed]
  44. Marofi, F.; Achmad, H.; Bokov, D.; Abdelbasset, W.K.; Alsadoon, Z.; Chupradit, S.; Suksatan, W.; Shariatzadeh, S.; Hasanpoor, Z.; Yazdanifar, M.; et al. Hurdles to breakthrough in CAR T cell therapy of solid tumors. Stem. Cell Res. 2022, 13, 140. [Google Scholar] [CrossRef] [PubMed]
  45. Safarzadeh Kozani, P.; Safarzadeh Kozani, P.; Ahmadi Najafabadi, M.; Yousefi, F.; Mirarefin, S.M.J.; Rahbarizadeh, F. Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells from Hero to Zero? Front. Immunol. 2022, 13, 795164. [Google Scholar] [CrossRef] [PubMed]
  46. Murad, J.P.; Tilakawardane, D.; Park, A.K.; Lopez, L.S.; Young, C.A.; Gibson, J.; Yamaguchi, Y.; Lee, H.J.; Kennewick, K.T.; Gittins, B.J.; et al. Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity. Mol. Ther. 2021, 29, 2335–2349. [Google Scholar] [CrossRef]
  47. Huang, M.; Xiong, D.; Pan, J.; Zhang, Q.; Sei, S.; Shoemaker, R.H.; Lubet, R.A.; Montuenga, L.M.; Wang, Y.; Slusher, B.S.; et al. Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer. Adv. Sci. 2022, 9, e2105885. [Google Scholar] [CrossRef]
  48. Cha, S.E.; Kujawski, M.; Yazaki, P.J.; Brown, C.; Shively, J.E. Tumor regression and immunity in combination therapy with anti-CEA chimeric antigen receptor T cells and anti-CEA-IL2 immunocytokine. Oncoimmunology 2021, 10, 1899469. [Google Scholar] [CrossRef]
  49. Feng, Z.; He, X.; Zhang, X.; Wu, Y.; Xing, B.; Knowles, A.; Shan, Q.; Miller, S.; Hojnacki, T.; Ma, J.; et al. Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. Nat. Cancer 2022, 3, 581–594. [Google Scholar] [CrossRef]
  50. Andrea, A.E.; Chiron, A.; Bessoles, S.; Hacein-Bey-Abina, S. Engineering Next-Generation CAR-T Cells for Better Toxicity Management. Int. J. Mol. Sci. 2020, 21, 8620. [Google Scholar] [CrossRef]
  51. Xu, J.; Meng, Q.; Sun, H.; Zhang, X.; Yun, J.; Li, B.; Wu, S.; Li, X.; Yang, H.; Zhu, H.; et al. HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer. Cell Death Dis. 2021, 12, 1109. [Google Scholar] [CrossRef] [PubMed]
  52. Povoski, S.P.; Hatzaras, I.S.; Mojzisik, C.M.; Martin, E.W., Jr. Oncologic theranostics: Recognition of this concept in antigen-directed cancer therapy for colorectal cancer with anti-TAG-72 monoclonal antibodies. Expert. Rev. Mol. Diagn. 2011, 11, 667–670. [Google Scholar] [CrossRef] [PubMed]
  53. Magee, M.S.; Abraham, T.S.; Baybutt, T.R.; Flickinger, J.C., Jr.; Ridge, N.A.; Marszalowicz, G.P.; Prajapati, P.; Hersperger, A.R.; Waldman, S.A.; Snook, A.E. Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases. Cancer Immunol. Res. 2018, 6, 509–516. [Google Scholar] [CrossRef] [PubMed]
  54. Deng, X.; Gao, F.; Li, N.; Li, Q.; Zhou, Y.; Yang, T.; Cai, Z.; Du, P.; Chen, F.; Cai, J. Antitumor activity of NKG2D CAR-T cells against human colorectal cancer cells in vitro and in vivo. Am. J. Cancer Res. 2019, 9, 945–958. [Google Scholar]
  55. Kim, J.H.; Park, S.Y.; Jeon, S.E.; Choi, J.H.; Lee, C.J.; Jang, T.Y.; Yun, H.J.; Lee, Y.; Kim, P.; Cho, S.H.; et al. DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis. Theranostics 2022, 12, 5258–5271. [Google Scholar] [CrossRef]
  56. Sureban, S.M.; Berahovich, R.; Zhou, H.; Xu, S.; Wu, L.; Ding, K.; May, R.; Qu, D.; Bannerman-Menson, E.; Golubovskaya, V.; et al. DCLK1 Monoclonal Antibody-Based CAR-T Cells as a Novel Treatment Strategy against Human Colorectal Cancers. Cancers 2019, 12, 54. [Google Scholar] [CrossRef]
  57. Zhao, W.; Jia, L.; Zhang, M.; Huang, X.; Qian, P.; Tang, Q.; Zhu, J.; Feng, Z. The killing effect of novel bi-specific Trop2/PD-L1 CAR-T cell targeted gastric cancer. Am. J. Cancer Res. 2019, 9, 1846–1856. [Google Scholar]
  58. Jin, L.; Tao, H.; Karachi, A.; Long, Y.; Hou, A.Y.; Na, M.; Dyson, K.A.; Grippin, A.J.; Deleyrolle, L.P.; Zhang, W.; et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat. Commun. 2019, 10, 4016. [Google Scholar] [CrossRef]
  59. Gonzalez-Mazon, I.; Sanchez-Bilbao, L.; Martin-Varillas, J.L.; Garcia-Castano, A.; Delgado-Ruiz, M.; Bernat Pina, I.; Hernandez, J.L.; Castaneda, S.; Llorca, J.; Gonzalez-Gay, M.A.; et al. Immune-related adverse events in patients with solid-organ tumours treated with immunotherapy: A 3-year study of 102 cases from a single centre. Clin. Exp. Rheumatol. 2021, 39, 612–620. [Google Scholar] [CrossRef]
  60. Kartolo, A.; Holstead, R.; Khalid, S.; Emack, J.; Hopman, W.; Baetz, T. Safety of Immunotherapy Rechallenge After Immune-related Adverse Events in Patients with Advanced Cancer. J. Immunother. 2021, 44, 41–48. [Google Scholar] [CrossRef]
  61. Presotto, E.M.; Rastrelli, G.; Desideri, I.; Scotti, V.; Gunnella, S.; Pimpinelli, N.; Vaccher, E.; Bearz, A.; Di Costanzo, F.; Bruggia, M.; et al. Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: Results of a large multicentre study. J. Endocrinol. Investig. 2020, 43, 337–345. [Google Scholar] [CrossRef] [PubMed]
  62. Su, Q.; Zhang, X.C.; Wang, D.Y.; Zhang, H.R.; Zhu, C.; Hou, Y.L.; Liu, J.L.; Gao, Z.H. The risk of immune-related endocrine disorders associated with anti-PD-1 inhibitors therapy for solid tumors: A systematic review and meta-analysis. Int. Immunopharmacol. 2018, 59, 328–338. [Google Scholar] [CrossRef] [PubMed]
  63. Gu, L.; Khadaroo, P.A.; Su, H.; Kong, L.; Chen, L.; Wang, X.; Li, X.; Zhu, H.; Zhong, X.; Pan, J.; et al. The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): A systematic review and meta-analysis. BMC Cancer 2019, 19, 559. [Google Scholar] [CrossRef] [PubMed]
  64. Dimitriou, F.; Mangana, J.; Micaletto, S.; Braun, R.P.; Dummer, R. Cytokine release syndrome as an important differential diagnosis of severe skin toxicity with organ damage during switch from immunotherapy to targeted therapy in metastatic melanoma. Melanoma Res. 2019, 29, 107–108. [Google Scholar] [CrossRef]
  65. Liu, Z.; Zhang, Y.; Shi, C.; Zhou, X.; Xu, K.; Jiao, D.; Sun, Z.; Han, X. A novel immune classification reveals distinct immune escape mechanism and genomic alterations: Implications for immunotherapy in hepatocellular carcinoma. J. Transl. Med. 2021, 19, 5. [Google Scholar] [CrossRef] [PubMed]
  66. Huang, H.; Zhou, J.; Chen, H.; Li, J.; Zhang, C.; Jiang, X.; Ni, C. The immunomodulatory effects of endocrine therapy in breast cancer. J. Exp. Clin. Cancer Res. 2021, 40, 19. [Google Scholar] [CrossRef] [PubMed]
  67. Siwicki, M.; Gort-Freitas, N.A.; Messemaker, M.; Bill, R.; Gungabeesoon, J.; Engblom, C.; Zilionis, R.; Garris, C.; Gerhard, G.M.; Kohl, A.; et al. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy. Sci. Immunol. 2021, 6, eabi7083. [Google Scholar] [CrossRef]
  68. Mitropoulou, G.; Daccord, C.; Sauty, A.; Pasche, A.; Egger, B.; Aedo Lopez, V.; Letovanec, I.; Beigelman-Aubry, C.; Nicod, L.P.; Lazor, R. Immunotherapy-Induced Airway Disease: A New Pattern of Lung Toxicity of Immune Checkpoint Inhibitors. Respiration 2020, 99, 181–186. [Google Scholar] [CrossRef]
  69. Haeuser, L.; Marchese, M.; Cone, E.B.; Noldus, J.; Bayliss, G.; Kilbridge, K.L.; Trinh, Q.D. Nephrotoxicity in immune checkpoint inhibitor therapy: A pharmacovigilance study. Nephrol. Dial. Transpl. 2021, 37, 1310–1316. [Google Scholar] [CrossRef]
  70. Zhao, Z.; Zhang, C.; Zhou, L.; Dong, P.; Shi, L. Immune Checkpoint Inhibitors and Neurotoxicity. Curr. Neuropharmacol. 2021, 19, 1246–1263. [Google Scholar] [CrossRef]
  71. Stower, H. Immunotherapy for heart injury. Nat. Med. 2019, 25, 1799. [Google Scholar] [CrossRef] [PubMed]
  72. Maloney, J.; Durham, S.; Skoner, D.; Dahl, R.; Bufe, A.; Bernstein, D.; Murphy, K.; Waserman, S.; Berman, G.; White, M.; et al. Safety of sublingual immunotherapy Timothy grass tablet in subjects with allergic rhinitis with or without conjunctivitis and history of asthma. Allergy 2015, 70, 302–309. [Google Scholar] [CrossRef] [PubMed]
  73. Kostine, M.; Finckh, A.; Bingham, C.O.; Visser, K.; Leipe, J.; Schulze-Koops, H.; Choy, E.H.; Benesova, K.; Radstake, T.; Cope, A.P.; et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann. Rheum. Dis. 2021, 80, 36–48. [Google Scholar] [CrossRef]
  74. Flowers, S.A.; Bhat, S.; Lee, J.C. Potential Implications of Gut Microbiota in Drug Pharmacokinetics and Bioavailability. Pharmacotherapy 2020, 40, 704–712. [Google Scholar] [CrossRef] [PubMed]
  75. Zhang, J.; Zhang, J.; Wang, R. Gut microbiota modulates drug pharmacokinetics. Drug Metab. Rev. 2018, 50, 357–368. [Google Scholar] [CrossRef]
  76. Zimmermann, M.; Zimmermann-Kogadeeva, M.; Wegmann, R.; Goodman, A.L. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science 2019, 363, eaat9931. [Google Scholar] [CrossRef]
  77. Ciccolini, J.; Mercier, C.; Blachon, M.F.; Favre, R.; Durand, A.; Lacarelle, B. A simple and rapid high-performance liquid chromatographic (HPLC) method for 5-fluorouracil (5-FU) assay in plasma and possible detection of patients with impaired dihydropyrimidine dehydrogenase (DPD) activity. J. Clin. Pharm. 2004, 29, 307–315. [Google Scholar] [CrossRef]
  78. Zimmermann, M.; Zimmermann-Kogadeeva, M.; Wegmann, R.; Goodman, A.L. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 2019, 570, 462–467. [Google Scholar] [CrossRef]
  79. Liu, J.R.; Miao, H.; Deng, D.Q.; Vaziri, N.D.; Li, P.; Zhao, Y.Y. Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation. Cell Mol. Life Sci. 2021, 78, 909–922. [Google Scholar] [CrossRef]
  80. Blasco, T.; Perez-Burillo, S.; Balzerani, F.; Hinojosa-Nogueira, D.; Lerma-Aguilera, A.; Pastoriza, S.; Cendoya, X.; Rubio, A.; Gosalbes, M.J.; Jimenez-Hernandez, N.; et al. An extended reconstruction of human gut microbiota metabolism of dietary compounds. Nat. Commun. 2021, 12, 4728. [Google Scholar] [CrossRef]
  81. Qiu, T.; Liu, L.; Zhou, H.; Sheng, H.; He, Y.; Liu, M.; Cai, H. Analysis of endometrial microbiota in intrauterine adhesion by high-throughput sequencing. Ann. Transl. Med. 2021, 9, 195. [Google Scholar] [CrossRef] [PubMed]
  82. Galyean, S.; Sawant, D.; Shin, A.C. Immunometabolism, Micronutrients, and Bariatric Surgery: The Use of Transcriptomics and Microbiota-Targeted Therapies. Mediat. Inflamm. 2020, 2020, 8862034. [Google Scholar] [CrossRef] [PubMed]
  83. Mokkala, K.; Paulin, N.; Houttu, N.; Koivuniemi, E.; Pellonpera, O.; Khan, S.; Pietila, S.; Tertti, K.; Elo, L.L.; Laitinen, K. Metagenomics analysis of gut microbiota in response to diet intervention and gestational diabetes in overweight and obese women: A randomised, double-blind, placebo-controlled clinical trial. Gut 2021, 70, 309–318. [Google Scholar] [CrossRef] [PubMed]
  84. Khan, S.; Hauptman, R.; Kelly, L. Engineering the Microbiome to Prevent Adverse Events: Challenges and Opportunities. Annu. Rev. Pharm. Toxicol. 2021, 61, 159–179. [Google Scholar] [CrossRef] [PubMed]
  85. Sivan, A.; Corrales, L.; Hubert, N.; Williams, J.B.; Aquino-Michaels, K.; Earley, Z.M.; Benyamin, F.W.; Lei, Y.M.; Jabri, B.; Alegre, M.L.; et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015, 350, 1084–1089. [Google Scholar] [CrossRef] [PubMed]
  86. Yi, M.; Yu, S.; Qin, S.; Liu, Q.; Xu, H.; Zhao, W.; Chu, Q.; Wu, K. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J. Hematol. Oncol. 2018, 11, 47. [Google Scholar] [CrossRef]
  87. Chaput, N.; Lepage, P.; Coutzac, C.; Soularue, E.; Le Roux, K.; Monot, C.; Boselli, L.; Routier, E.; Cassard, L.; Collins, M.; et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 2017, 28, 1368–1379. [Google Scholar] [CrossRef]
  88. Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 2009, 45, 228–247. [Google Scholar] [CrossRef]
  89. Derosa, L.; Routy, B.; Kroemer, G.; Zitvogel, L. The intestinal microbiota determines the clinical efficacy of immune checkpoint blockers targeting PD-1/PD-L1. Oncoimmunology 2018, 7, e1434468. [Google Scholar] [CrossRef]
  90. Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C.P.M.; Alou, M.T.; Daillere, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M.P.; et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018, 359, 91–97. [Google Scholar] [CrossRef]
  91. Sears, C.L.; Pardoll, D.M. The intestinal microbiome influences checkpoint blockade. Nat. Med. 2018, 24, 254–255. [Google Scholar] [CrossRef] [PubMed]
  92. Frankel, A.E.; Coughlin, L.A.; Kim, J.; Froehlich, T.W.; Xie, Y.; Frenkel, E.P.; Koh, A.Y. Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients. Neoplasia 2017, 19, 848–855. [Google Scholar] [CrossRef] [PubMed]
  93. Zhang, M.; Zhang, Y.; Han, Y.; Zhao, X.; Sun, Y. Characteristics of pathogenic microbes in lung microenvironment of lung cancer patients without respiratory infection. J BUON 2021, 26, 1862–1870. [Google Scholar] [PubMed]
  94. Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M.L.; Luke, J.J.; Gajewski, T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018, 359, 104–108. [Google Scholar] [CrossRef] [PubMed]
  95. Ekmekciu, I.; von Klitzing, E.; Fiebiger, U.; Escher, U.; Neumann, C.; Bacher, P.; Scheffold, A.; Kuhl, A.A.; Bereswill, S.; Heimesaat, M.M. Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice. Front. Immunol. 2017, 8, 397. [Google Scholar] [CrossRef] [PubMed]
  96. Oh, J.; Unutmaz, D. Immune cells for microbiota surveillance. Science 2019, 366, 419–420. [Google Scholar] [CrossRef]
  97. Bachem, A.; Makhlouf, C.; Binger, K.J.; de Souza, D.P.; Tull, D.; Hochheiser, K.; Whitney, P.G.; Fernandez-Ruiz, D.; Dahling, S.; Kastenmuller, W.; et al. Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8(+) T Cells. Immunity 2019, 51, 285–297.e5. [Google Scholar] [CrossRef]
  98. Teng, L.; Wang, K.; Chen, W.; Wang, Y.S.; Bi, L. HYR-2 plays an anti-lung cancer role by regulating PD-L1 and Akkermansia muciniphila. Pharm. Res 2020, 160, 105086. [Google Scholar] [CrossRef]
  99. Derosa, L.; Routy, B.; Fidelle, M.; Iebba, V.; Alla, L.; Pasolli, E.; Segata, N.; Desnoyer, A.; Pietrantonio, F.; Ferrere, G.; et al. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients. Eur. Urol. 2020, 78, 195–206. [Google Scholar] [CrossRef]
  100. Routy, B.; Gopalakrishnan, V.; Daillere, R.; Zitvogel, L.; Wargo, J.A.; Kroemer, G. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 2018, 15, 382–396. [Google Scholar] [CrossRef]
  101. Ishikawa, D.; Sasaki, T.; Takahashi, M.; Kuwahara-Arai, K.; Haga, K.; Ito, S.; Okahara, K.; Nakajima, A.; Shibuya, T.; Osada, T.; et al. The Microbial Composition of Bacteroidetes Species in Ulcerative Colitis Is Effectively Improved by Combination Therapy With Fecal Microbiota Transplantation and Antibiotics. Inflamm. Bowel Dis. 2018, 24, 2590–2598. [Google Scholar] [CrossRef] [PubMed]
  102. Esfahani, K.; Hudson, M.; Batist, G. Tofacitinib for Refractory Immune-Related Colitis from PD-1 Therapy. N. Engl. J. Med. 2020, 382, 2374–2375. [Google Scholar] [CrossRef] [PubMed]
  103. Sakellariou, S.; Zouki, D.N.; Ziogas, D.C.; Pouloudi, D.; Gogas, H.; Delladetsima, I. Granulomatous colitis in a patient with metastatic melanoma under immunotherapy: A case report and literature review. BMC Gastroenterol. 2021, 21, 227. [Google Scholar] [CrossRef] [PubMed]
  104. Wan, X.; Song, M.; Wang, A.; Zhao, Y.; Wei, Z.; Lu, Y. Microbiome Crosstalk in Immunotherapy and Antiangiogenesis Therapy. Front. Immunol. 2021, 12, 747914. [Google Scholar] [CrossRef]
  105. Sakurai, T.; De Velasco, M.A.; Sakai, K.; Nagai, T.; Nishiyama, H.; Hashimoto, K.; Uemura, H.; Kawakami, H.; Nakagawa, K.; Ogata, H.; et al. Integrative analysis of gut microbiome and host transcriptomes reveals associations between treatment outcomes and immunotherapy-induced colitis. Mol. Oncol. 2021, 16, 1493–1507. [Google Scholar] [CrossRef]
  106. Zhou, C.B.; Zhou, Y.L.; Fang, J.Y. Gut Microbiota in Cancer Immune Response and Immunotherapy. Trends Cancer 2021, 7, 647–660. [Google Scholar] [CrossRef]
  107. Vetizou, M.; Daillere, R.; Zitvogel, L. The role of intestinal microbiota in the response to anti-tumor therapies. Med. Sci. 2016, 32, 974–982. [Google Scholar] [CrossRef]
  108. Wang, G.; Yu, Y.; Wang, Y.Z.; Wang, J.J.; Guan, R.; Sun, Y.; Shi, F.; Gao, J.; Fu, X.L. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. J. Cell Physiol. 2019, 234, 17023–17049. [Google Scholar] [CrossRef]
  109. Temraz, S.; Nassar, F.; Nasr, R.; Charafeddine, M.; Mukherji, D.; Shamseddine, A. Gut Microbiome: A Promising Biomarker for Immunotherapy in Colorectal Cancer. Int. J. Mol. Sci. 2019, 20, 4155. [Google Scholar] [CrossRef]
  110. Dai, Z.; Zhang, J.; Wu, Q.; Fang, H.; Shi, C.; Li, Z.; Lin, C.; Tang, D.; Wang, D. Intestinal microbiota: A new force in cancer immunotherapy. Cell Commun. Signal 2020, 18, 90. [Google Scholar] [CrossRef]
  111. Wang, T.; Zheng, N.; Luo, Q.; Jiang, L.; He, B.; Yuan, X.; Shen, L. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front. Immunol. 2019, 10, 1235. [Google Scholar] [CrossRef]
  112. Sun, M.C.; Zhang, F.C.; Yin, X.; Cheng, B.J.; Zhao, C.H.; Wang, Y.L.; Zhang, Z.Z.; Hao, H.W.; Zhang, T.H.; Ye, H.Q. Lactobacillus reuteri F-9-35 Prevents DSS-Induced Colitis by Inhibiting Proinflammatory Gene Expression and Restoring the Gut Microbiota in Mice. J. Food Sci. 2018, 83, 2645–2652. [Google Scholar] [CrossRef] [PubMed]
  113. Mayer, C.; Brachhold, K. Molecular Nutrition-From Gut Microbiota to Metabolomics and Inter-Individual Nutrition. Mol. Nutr. Food Res. 2019, 63, e1970005. [Google Scholar] [CrossRef] [PubMed]
  114. Ferrere, G.; Tidjani Alou, M.; Liu, P.; Goubet, A.G.; Fidelle, M.; Kepp, O.; Durand, S.; Iebba, V.; Fluckiger, A.; Daillere, R.; et al. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight 2021, 6, e145207. [Google Scholar] [CrossRef] [PubMed]
  115. McQuade, J.L.; Daniel, C.R.; Helmink, B.A.; Wargo, J.A. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 2019, 20, e77–e91. [Google Scholar] [CrossRef]
  116. Benech, N.; Sokol, H. Fecal microbiota transplantation in gastrointestinal disorders: Time for precision medicine. Genome Med. 2020, 12, 58. [Google Scholar] [CrossRef]
  117. Baunwall, S.M.D.; Lee, M.M.; Eriksen, M.K.; Mullish, B.H.; Marchesi, J.R.; Dahlerup, J.F.; Hvas, C.L. Faecal microbiota transplantation for recurrent Clostridioides difficile infection: An updated systematic review and meta-analysis. EClinicalMedicine 2020, 29-30, 100642. [Google Scholar] [CrossRef]
  118. Stojek, M.; Jablonska, A.; Adrych, K. The Role of Fecal Microbiota Transplantation in the Treatment of Inflammatory Bowel Disease. J. Clin. Med. 2021, 10, 4055. [Google Scholar] [CrossRef]
  119. He, Y.; Xu, R.; Wang, W.; Zhang, J.; Hu, X. Probiotics, prebiotics, antibiotic, Chinese herbal medicine, and fecal microbiota transplantation in irritable bowel syndrome: Protocol for a systematic review and network meta-analysis. Medicine 2020, 99, e21502. [Google Scholar] [CrossRef]
  120. Bajaj, J.S.; Shamsaddini, A.; Fagan, A.; Sterling, R.K.; Gavis, E.; Khoruts, A.; Fuchs, M.; Lee, H.; Sikaroodi, M.; Gillevet, P.M. Fecal Microbiota Transplant in Cirrhosis Reduces Gut Microbial Antibiotic Resistance Genes: Analysis of Two Trials. Hepatol. Commun. 2021, 5, 258–271. [Google Scholar] [CrossRef]
  121. Baruch, E.N.; Youngster, I.; Ben-Betzalel, G.; Ortenberg, R.; Lahat, A.; Katz, L.; Adler, K.; Dick-Necula, D.; Raskin, S.; Bloch, N.; et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021, 371, 602–609. [Google Scholar] [CrossRef] [PubMed]
  122. Baruch, K.; Deczkowska, A.; Rosenzweig, N.; Tsitsou-Kampeli, A.; Sharif, A.M.; Matcovitch-Natan, O.; Kertser, A.; David, E.; Amit, I.; Schwartz, M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 2016, 22, 135–137. [Google Scholar] [CrossRef] [PubMed]
  123. Baruch, E.N.; Gaglani, T.; Wargo, J.A. Fecal microbiota transplantation as a mean of overcoming immunotherapy-resistant cancers-hype or hope? Adv. Med. Oncol. 2021, 13, 17588359211045853. [Google Scholar] [CrossRef] [PubMed]
  124. Koo, H.; Morrow, C.D. Incongruence between dominant commensal donor microbes in recipient feces post fecal transplant and response to anti-PD-1 immunotherapy. BMC Microbiol. 2021, 21, 251. [Google Scholar] [CrossRef] [PubMed]
  125. Davar, D.; Dzutsev, A.K.; McCulloch, J.A.; Rodrigues, R.R.; Chauvin, J.M.; Morrison, R.M.; Deblasio, R.N.; Menna, C.; Ding, Q.; Pagliano, O.; et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021, 371, 595–602. [Google Scholar] [CrossRef]
  126. Ni, J.; Shen, T.D.; Chen, E.Z.; Bittinger, K.; Bailey, A.; Roggiani, M.; Sirota-Madi, A.; Friedman, E.S.; Chau, L.; Lin, A.; et al. A role for bacterial urease in gut dysbiosis and Crohn’s disease. Sci. Transl. Med. 2017, 9, eaah6888. [Google Scholar] [CrossRef]
  127. Torres-Maravilla, E.; Boucard, A.S.; Mohseni, A.H.; Taghinezhad, S.S.; Cortes-Perez, N.G.; Bermudez-Humaran, L.G. Role of Gut Microbiota and Probiotics in Colorectal Cancer: Onset and Progression. Microorganisms 2021, 9, 1021. [Google Scholar] [CrossRef]
  128. Walker, A. Intestinal colonization and programming of the intestinal immune response. J. Clin. Gastroenterol. 2014, 48 (Suppl. 1), S8–S11. [Google Scholar] [CrossRef]
  129. Zitvogel, L.; Derosa, L.; Kroemer, G. Modulation of cancer immunotherapy by dietary fibers and over-the-counter probiotics. Cell Metab. 2022, 34, 350–352. [Google Scholar] [CrossRef]
  130. Vale, G.C.; Mota, B.I.S.; Ando-Suguimoto, E.S.; Mayer, M.P.A. Effect of Probiotics Lactobacillus acidophilus and Lacticaseibacillus rhamnosus on Antibacterial Response Gene Transcription of Human Peripheral Monocytes. Probiotics Antimicrob. Proteins 2021. [Google Scholar] [CrossRef]
  131. Hibberd, A.A.; Lyra, A.; Ouwehand, A.C.; Rolny, P.; Lindegren, H.; Cedgard, L.; Wettergren, Y. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol. 2017, 4, e000145. [Google Scholar] [CrossRef] [PubMed]
  132. Bi, H.; Tian, Y.; Song, C.; Li, J.; Liu, T.; Chen, Z.; Chen, C.; Huang, Y.; Zhang, Y. Urinary microbiota-a potential biomarker and therapeutic target for bladder cancer. J. Med. Microbiol. 2019, 68, 1471–1478. [Google Scholar] [CrossRef] [PubMed]
  133. Tawfick, M.M.; Xie, H.; Zhao, C.; Shao, P.; Farag, M.A. Inulin fructans in diet: Role in gut homeostasis, immunity, health outcomes and potential therapeutics. Int. J. Biol. Macromol. 2022, 208, 948–961. [Google Scholar] [CrossRef] [PubMed]
  134. Sakai, Y.; Hamano, H.; Ochi, H.; Abe, F.; Masuda, K.; Iino, H. Lactulose ingestion causes an increase in the abundance of gut-resident bifidobacteria in Japanese women: A randomised, double-blind, placebo-controlled crossover trial. Benef Microbes 2021, 12, 43–53. [Google Scholar] [CrossRef] [PubMed]
  135. Pal, R.; Athamneh, A.I.M.; Deshpande, R.; Ramirez, J.A.R.; Adu, K.T.; Muthuirulan, P.; Pawar, S.; Biazzo, M.; Apidianakis, Y.; Sundekilde, U.K.; et al. Probiotics: Insights and new opportunities for Clostridioides difficile intervention. Crit. Rev. Microbiol. 2022, 1–21. [Google Scholar] [CrossRef]
  136. Tanoue, T.; Morita, S.; Plichta, D.R.; Skelly, A.N.; Suda, W.; Sugiura, Y.; Narushima, S.; Vlamakis, H.; Motoo, I.; Sugita, K.; et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 2019, 565, 600–605. [Google Scholar] [CrossRef]
  137. Lamberte, L.E.; van Schaik, W. Antibiotic resistance in the commensal human gut microbiota. Curr. Opin. Microbiol. 2022, 68, 102150. [Google Scholar] [CrossRef]
  138. Blaser, M.J. Antibiotic use and its consequences for the normal microbiome. Science 2016, 352, 544–545. [Google Scholar] [CrossRef]
  139. Pinato, D.J.; Howlett, S.; Ottaviani, D.; Urus, H.; Patel, A.; Mineo, T.; Brock, C.; Power, D.; Hatcher, O.; Falconer, A.; et al. Association of Prior Antibiotic Treatment with Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer. JAMA Oncol. 2019, 5, 1774–1778. [Google Scholar] [CrossRef]
  140. Kaderbhai, C.; Richard, C.; Fumet, J.D.; Aarnink, A.; Foucher, P.; Coudert, B.; Favier, L.; Lagrange, A.; Limagne, E.; Boidot, R.; et al. Antibiotic Use Does Not Appear to Influence Response to Nivolumab. Anticancer Res. 2017, 37, 3195–3200. [Google Scholar] [CrossRef]
Cancers 14 04796 g001 550
Figure 1. Immune-related adverse events of various organs or tissues caused by cancer immunotherapy. The immune adverse events mainly involved the skin, gastrointestinal tract, endocrine glands, liver, lungs, kidneys, nerves, heart, eyes, and musculoskeletal. The addition of the gut microbiota is expected to optimize the efficacy of cancer immunotherapy.
Figure 1. Immune-related adverse events of various organs or tissues caused by cancer immunotherapy. The immune adverse events mainly involved the skin, gastrointestinal tract, endocrine glands, liver, lungs, kidneys, nerves, heart, eyes, and musculoskeletal. The addition of the gut microbiota is expected to optimize the efficacy of cancer immunotherapy.
Cancers 14 04796 g001
Cancers 14 04796 g002 550
Figure 2. Differences in intestinal microbiota enrichment in ICIs (anti-PD-1/PD-L1 or anti-CTLA-4). Sankey diagrams provide visual clues to the enrichment characteristics of microorganisms in different ICIs. Blue band: the bacterial microbiota enriched in patients responding to ICIs, including Akkermansia muciniophila, Bifidobacterium species and Bacillus species, etc. Red band: the bacterial microbiota enriched in patients who did not respond to ICIs, including Staphylococcus haemolyticus, Bacteriodales, and Prevotella histicola, among others. The number in brackets indicates the source of the reference. (1) [87] (2) [92] (3) [10] (4) [94] (5) [100] (6) [90] (7) [109].
Figure 2. Differences in intestinal microbiota enrichment in ICIs (anti-PD-1/PD-L1 or anti-CTLA-4). Sankey diagrams provide visual clues to the enrichment characteristics of microorganisms in different ICIs. Blue band: the bacterial microbiota enriched in patients responding to ICIs, including Akkermansia muciniophila, Bifidobacterium species and Bacillus species, etc. Red band: the bacterial microbiota enriched in patients who did not respond to ICIs, including Staphylococcus haemolyticus, Bacteriodales, and Prevotella histicola, among others. The number in brackets indicates the source of the reference. (1) [87] (2) [92] (3) [10] (4) [94] (5) [100] (6) [90] (7) [109].
Cancers 14 04796 g002
Table
Table 1. Some solid tumors receiving immunotherapy.
Table 1. Some solid tumors receiving immunotherapy.
ICIsCancerResultsReferences
Anti-PD-1NivolumabAdvanced cervical cancer36% patients had stable disease (9/25; 90% CI, 20.2–54.4%) for a median of 5.7 months. Estimated PFS and OS at 6 months were 16% and 78.4%.[23]
PembrolizumabNSCLCHalf-year PFS:22%; median PFS:2.8 months (95% CI: 1.5–4.1); median OS: 11.7 months (95% CI: 7.6–13.4).[24]
CemiplimabAdvanced squamous cell carcinomasPD-L1 expression was ≥1% in 18% patients and <1% in 11% of patients.[25]
Anti-PD-L1AtezolizumabAdvanced triple-negative breast cancerMedian survival to progression and overall survival were 5.5 months (95% CI, 5.1–7.7 months) and 14.7 months (95% CI, 10.1, not evaluable).[26]
AvelumabAdvanced Merkel cell cancerORR:48.0%; median duration of treatment:7.4 months (1.0–41.7 months).[27]
DurvalumabNSCLCMedian PFS:17.5 months (95% CI, 13.2–24.9); median OS:47 months (95%CI, 47 [NR]).[28]
Anti-CTLA4IpilimumabMetastatic melanomaSurvival rates at 5 years in patients were OS 11%.[29]
CombinationIpilimumab + nivolumabMetastatic CRCPFS:76% (9 months) and 71% (12 months); respective OS: 87% and 85%.[30]
Table
Table 2. Common immune-related adverse events.
Table 2. Common immune-related adverse events.
Systemic or Tissue ToxicityClinical ManifestationTreatment MeasuresReferences
SkinRash, itchingSymptomatic treatment (topical corticosteroids and oral antihistamines).[64]
Gastrointestinal tractDiarrhea, colitisRehydrate, rule out infection, and administer oral or intravenous corticosteroids. Colonoscopy or sigmoidoscopy.[65]
EndocrineThyroid, pituitary, or adrenal gland damageDuring ICIs, thyroid function is regularly monitored.[66]
LiverAsymptomatic elevations in ALT, AST, or total bilirubinWith oral corticosteroids, immune-mediated hepatitis usually resolves within 4–6 weeks.[67]
LungDry cough, progressive difficulty breathingNearly 75% of patients may require discontinuation of ICIs.[68]
KidneyAsymptomatic elevation of creatinineCorticosteroid therapy and sparing immunotherapy are recommended. Renal biopsy is necessary for higher-grade events.[69]
NeurotoxicityFacial paralysis, optic neuritis, Guillain-Barre syndrome, myasthenia gravis, encephalitis, and aseptic meningitisSteroid therapy is used to relieve mild symptoms, but severe toxicity requires high doses or other therapies.[70]
CardiotoxicityHeart failure, cardiomyopathy, heart block, myocardial fibrosis, and myocarditisICIs were discontinued, and steroid therapy was initiated.[71]
EyeKeratitis, uveitis, conjunctivitis, and episcleritisTopical or systemic corticosteroid therapy.[72]
Muscle, Bone and RheumatologyVasculitis, inflammatory arthritis, and myositisLow-dose steroids have some effects.[73]
Table
Table 4. Related clinical trials of FMT in cancer immunotherapy.
Table 4. Related clinical trials of FMT in cancer immunotherapy.
NCT NumberTitleStatusConditionsInterventionsPhases
NCT05008861Gut Microbiota Reconstruction for NSCLC ImmunotherapyNot yet recruitingNon-Small Cell Lung CancerProcedure: Capsulized Fecal Microbiota Transplant
Drug: Anti-PD-1/PD-L1
Drug: Platinum-based chemotherapy		Phase 1
NCT04924374Microbiota Transplant in Advanced Lung Cancer Treated with ImmunotherapyRecruitingLung CancerDietary Supplement: Microbiota Transplant plus anti-PD-1 therapy
Drug: anti-PD-1 therapy		Not Applicable
NCT04729322Fecal Microbiota Transplant and Re-introduction of Anti-PD-1 Therapy (Pembrolizumab or Nivolumab) for the Treatment of Metastatic Colorectal Cancer in Anti-PD-1 Non-respondersRecruitingMetastatic Colorectal Adenocarcinoma
Metastatic Small Intestinal Adenocarcinoma
Stage IV Colorectal Cancer		Procedure: Fecal Microbiota Transplantation
Drug: Metronidazole
Biological: Nivolumab/Pembrolizumab		Early Phase 1
NCT03353402Fecal Microbiota Transplantation (FMT) in Metastatic Melanoma Patients Who Failed ImmunotherapyRecruitingMelanoma Stage Iv
Unresectable Stage III Melanoma		Procedure: Fecal Microbiota Transplant (FMT)Phase 1
NCT03772899Fecal Microbial Transplantation in Combination with Immunotherapy in Melanoma Patients (MIMic)RecruitingMelanomaDrug: Fecal Microbial TransplantationPhase 1
NCT04758507Fecal Microbiota Transplantation to Improve Efficacy of Immune Checkpoint Inhibitors in Renal Cell CarcinomaRecruitingRenal Cell CarcinomaBiological: donor FMT
Other: Placebo FMT		Phase 1
Phase 2
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Dai, Z.; Fu, J.; Peng, X.; Tang, D.; Song, J. Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy. Cancers 2022, 14, 4796. https://doi.org/10.3390/cancers14194796

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Dai Z, Fu J, Peng X, Tang D, Song J. Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy. Cancers. 2022; 14(19):4796. https://doi.org/10.3390/cancers14194796

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Dai, Zhujiang, Jihong Fu, Xiang Peng, Dong Tang, and Jinglue Song. 2022. "Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy" Cancers 14, no. 19: 4796. https://doi.org/10.3390/cancers14194796

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