Search Results (80)

Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT. Full article

Immunotherapy has revolutionized cancer treatment; however, the availability of cost-effective blood-based biomarkers for prognostic and predictive factors of immune treatment in patients with solid tumors remains limited. Due to low cost and easy accessibility, blood-based biomarkers should constitute an essential component of studies to optimize and monitor immunotherapy. Currently available markers that can be measured in peripheral blood include total monocyte count, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), relative eosinophil count, cytokine levels (such as IL-6, IL-8, and IL-10), lactate dehydrogenase (LDH), C-reactive protein (CRP), soluble forms of CTLA-4 and PD-1 or PD-L1, as well as circulating tumor DNA (ctDNA). In our mini-review, we discuss the latest evidence indicating that routinely accessible peripheral blood parameters—such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and rheological parameters, which so far have been rarely considered for such an application, may be used as non-invasive biomarkers in cancer immunotherapy. Rheological parameters such as whole blood viscosity are influenced by several factors, such as hematocrit, aggregability and deformability of erythrocytes, and plasma viscosity, which is largely dependent on plasma proteins. Especially in cases where the set of symptoms indicates a high probability of hyperviscosity syndrome, blood rheological tests can lead to early diagnosis and treatment. Both biochemical and rheological parameters are prone to become novel and future standards for assessing immunotherapy among patients with solid tumors. Full article

Tumor cells and the tumor microenvironment (TME) produce factors, including neurotrophins, that induce axonogenesis and neurogenesis, and increase local nerve density. Proliferative growing cancer cell clusters and disseminated invasive tumor cells undergoing partial epithelial-to-mesenchymal transition (pEMT) can invade peripheral nerves. In the early stages of tumor–nerve interactions, Schwann cells (SCs) dedifferentiate, become activated and migrate to cancer cell nests; later, they induce pEMT in tumor cells and activate tumor cell migration along nerves. The SC–tumor–nerve interaction attracts myeloid-derived suppressor cells (MDSCs) and inflammatory monocytes, and the latter differentiate into macrophages. SCs and MDSCs are responsible for the activation of transforming growth factor-beta (TGF-beta) signaling. Intra-tumoral innervation is followed by perineural invasion (PNI), which has an unfavorable prognosis. What are the interventional options against PNI: local reduction in tumor nerves or inhibition of TGF-beta-related events, inhibition of downstream signaling of TGF-beta or immune activation, or intervention against immunosuppression? This systematic review is based on the Prisma 2009 search method and provides an overview of tumor–nerve interaction. Full article

Cancer is the most common malignancy, with over 2 million new cases and nearly 1.8 million deaths worldwide annually. Non-small-cell lung cancer (NSCLC) is the predominant subtype, accounting for the majority of cases. Myeloid-derived suppressor cells (MDSCs), which originate from monocytes and typically differentiate into macrophages and granulocytes, possess potent immunosuppressive capabilities. MDSCs regulate immune responses in various pathological conditions and are strongly associated with poor prognosis in cancer patients. This study aims to elucidate the complex interplay between MDSCs, immune cells, and tumours in the NSCLC tumour microenvironment (TME). By integrating single-cell RNA sequencing (scRNA-seq) data with bulk RNA sequencing (Bulk RNA-seq) data, we identified MDSCs as the target cell population and used Monocle software (v2.22.0) to infer their developmental trajectories. We identified key genes associated with MDSCs differentiation processes and classified MDSCs into seven distinct states based on their functional roles. Furthermore, we constructed a prognostic risk model based on the impact of MDSCs differentiation on NSCLC prognosis, utilizing Elastic Net regression and multivariate Cox regression analysis of Bulk RNA-seq data. The model’s performance and accuracy were validated using both internal and external validation sets. Additionally, we compared risk scores with clinical pathological features and the relationship between risk scores and key immune cells in the immune microenvironment, demonstrating the model’s clinical predictive value. We also explored how prognostic genes contribute to poor prognosis in NSCLC. Moreover, small molecule compounds targeting these prognostic genes were screened, and their anti-tumour effects were evaluated as potential therapeutic strategies for NSCLC treatment. This study not only reveals the complex regulatory mechanisms of MDSCs in the NSCLC immune microenvironment but also successfully constructs a prognostic risk model based on MDSCs differentiation states. The model demonstrates excellent clinical performance in predicting patient prognosis, effectively identifying high-risk patients and providing robust support for individualized treatment and immunotherapy decisions. Through association analyses with key immune cells in the immune microenvironment and clinical pathological features, our model can assist clinicians in formulating more precise treatment plans based on patients’ immune status and tumour characteristics. Furthermore, we identified small molecule compounds targeting these prognostic genes, providing novel and promising therapeutic targets for NSCLC, which could further enhance treatment efficacy and improve patients’ survival quality. Full article

Metastasis is the leading cause of cancer-related deaths. During the metastatic cascade, cancer cells tightly interact with immune cells influencing each other in the tumor microenvironment and systemically. Monocytes are important components of immune evasion and critical regulators of cancer progression. They circulate through the bloodstream and contribute to the formation of a pro-tumor microenvironment both in the tumor and pre-metastatic niche. Whereas monocyte participation in cancer development and response to therapy has been described extensively, its impact on metastasis remains a completely uncovered area. This review first summarizes data concerning the influence of monocytes on metastasis formation during their presence in the circulation, primary tumor, and pre-metastatic niche. We also highlight the latest examinations into the clinical relevance of targeting monocytes to prevent metastasis. Full article

Cancer cells are often described as voracious consumers of nutrients, with glucose frequently cited as a key energy source; however, their metabolic plasticity allows them to adapt and utilize various substrates, including lipids and amino acids, to sustain growth and survival. However, the metabolic demands of immune cells within the tumor microenvironment (TME) are less commonly discussed despite their critical role in shaping the immune response. In this review, we explored the intricate interplay between immunometabolism and innate immunity cells in gastrointestinal cancers. We focused on how metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, drive the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs), tumor-associated macrophages (TAMs) and innate lymphocyte subsets such as NK cells. These cells contribute to a hostile immune landscape, supporting tumor growth and evasion from immune surveillance in a phenomenon of tumor-derived immunosuppression. Additionally, we investigated the influence of dietary interventions on the metabolic reprogramming of these immune cells, highlighting how nutrition can modulate the TME. Finally, we discussed emerging therapeutic strategies that target metabolic vulnerabilities in MDSCs, TANs, NK cells, and monocytes, offering a novel avenue for enhancing antitumor immunity. By dissecting these mechanisms, we aim to provide insights into how metabolic pathways can be harnessed to improve cancer treatment outcomes. This review underscores the importance of understanding immunometabolism not only as a driver of immune suppression but also as a potential therapeutic target in gastrointestinal cancer. Full article

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment. Full article

Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11b⁺Ly6G⁻Ly6C⁻ myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction. Full article

Intra-articular ankle fracture (IAF) often leads to post-traumatic osteoarthritis (PTOA), resulting in significant long-term morbidity. While previous research has focused on the inflammatory cytokines and matrix metalloproteinases within the synovial fluid fracture hematoma (SFFH), the immune cell populations within SFFH that contribute to PTOA development remain underexplored. This study aimed to characterize the immune cell populations in SFFH to better understand their role in the inflammatory response and potential for inducing lasting cartilage damage. Twenty-four patients with IAF underwent surgical ankle aspiration to collect SFFH, which was analyzed using polychromatic flow cytometry. The analysis revealed that 72.8% of the CD45+ cells were lymphocytes, predominantly CD3+ T cells (76.5%), with 42.1% being CD4+ and 39.2% CD8+ T cells. Additionally, monocytes accounted for 21.2% of CD45+ cells, with small populations of natural killer cells and myeloid-derived suppressor cells also present. These findings emphasize the predominance of T cells, particularly CD4+ subsets, in the immune response following IAF. Understanding these dynamics is essential for developing targeted interventions to prevent PTOA. Future research should focus on elucidating the specific roles of these immune cell populations in PTOA progression and exploring potential therapeutic strategies. Full article

The interaction of myeloid-derived suppressor cells (MDSCs) with T cells within G-CSF-mobilized peripheral blood stem cell (PBSC) grafts in patients undergoing autologous or allogeneic hematopoietic stem cell transplantation remains to be elucidated. Through studying allo- and auto-PBSC grafts, we observed grafts containing large numbers of T cells and MDSCs with intergraft variability in their percentage and number. T cells from autologous grafts compared to allografts expressed relative higher percentages of inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT and BTLA. Autograft T cells had decreased cell proliferation and IFN-γ secretion, which supported the possible presence of T cell exhaustion. On the contrary, graft monocytic MDSCs (M-MDSCs) expressed multiple inhibitory receptor ligands, including PD-L1, CD86, Galectin-9, HVEM and CD155. The expression of inhibitory receptor ligands on M-MDSCs was correlated with their corresponding inhibitory receptors on T cells in the grafts. Isolated M-MDSCs had the ability to suppress T cell proliferation and IFN-γ secretion and/or promote Treg expansion. Blocking the PD-L1-PD-1 signaling pathway partially reversed the functions of M-MDSCs. Taken together, our data indicated that T cells and M-MDSCs in PBSC grafts express complementary inhibitory receptor–ligand pairing, which may impact the quality of immune recovery and clinical outcome post transplantation. Full article

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2⁺/CX3CR1⁺ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2⁺/CX3CR1⁺ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma. Full article

Background: In advanced head and neck cancer (HNC) patients, 50–60% experience loco-regional relapse and distant metastasis. Boron neutron capture therapy (BNCT) has shown remarkable therapeutic response in recurrent HNC, but there is still a 70% chance of local recurrence. This study aimed to identify a suitable liquid biomarker to assess patient response following BNCT. Myeloid-derived suppressor cells (MDSCs) are immune-suppressive cells that inhibit cytotoxic T cells. Circulating MDSC levels have been linked to the clinical stage and prognosis in HNSCC. Methods: Five patients with recurrent head and neck cancer underwent a treatment regimen that commenced with BNCT, followed by fractionated image-guided intensity-modulated radiotherapy (IG-IMRT). Liquid biopsy analysis via flow cytometry and tumor volume analysis by clinical imaging were conducted at three stages: before BNCT, before the first fraction of IG-IMRT, and one month after the last fraction of IG-IMRT. Results: Compared to other MDSC subtypes, monocytic MDSCs (M-MDSCs) exhibited a notable correlation with tumor volume. This strong correlation was observed at all testing time points except one month after BNCT treatment. Conclusions: This case series highlights a strong link between tumor size and circulating M-MDSC levels before BNCT and one month after the last IG-IMRT treatment in recurrent head and neck cancer patients. These results suggest that the level of circulating M-MDSCs could be a marker for monitoring tumor progression in recurrent HNC patients following radiation therapy, including BNCT. Full article

HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of immune cells including granulocytic (CD14neg/CD15+/HLA-DRneg) and monocytic subtypes (CD14+/CD15neg/HLA-DRneg). In the present study, we found a population of monocytes expressing the granulocyte marker CD15 that significantly increased in both peripheral blood (PB) and tumoral tissues of patients with colorectal cancer (CRC). Further phenotypical analysis confirmed the granulocytic-like features of this monocyte subpopulation that is associated with an increase in granulocyte–monocyte precursors (GMPs) in the PB of these patients (pts). Mechanistically, this granulocyte-like monocyte population suppressed NK cell activity by inducing TIGIT and engaging NKp30. Accordingly, an increased frequency of TIGIT+ NK cells with impaired functions was found in both the PB and tumoral tissue of CRC pts. Collectively, we provided new mechanistic explanations for tumor immune escape occurring in CRC by showing the increase in this new kind of MDSC, in both PB and CRC tissue, which is able to significantly impair the effector functions of NK cells, thereby representing a potential therapeutic target for cancer immunotherapy. Full article

The tumor microenvironment of glioblastoma IDH-wildtype is highly immune suppressive and is characterized by a strong component of myeloid-derived suppressor cells (MDSCs). To interfere with the immune suppressive functions of MDSCs, a comprehensive understanding on how MDSCs acquire their suppressive phenotype is essential. Previously, we and others have shown a distinct Sialic acid-binding immunoglobulin-like lectin (Siglec) receptor expression profile for MDSCs in glioblastoma. Siglec receptors can transmit inhibitory signals comparable to PD-1 and are suggested to act as glyco-immune checkpoints. Here, we investigated how glioma specific Siglec-sialic acid interactions influence myeloid immune suppressive functions. Co-culturing monocytes with glioblastoma cells induced CD163 expression on the monocytes. Upon desialylation of the glioblastoma cells, this induction of CD163 was hampered, and furthermore, the monocytes were now able to secrete higher amounts of IL-6 and TNFα compared to fully sialylated glioblastoma cells. Additionally, Siglec-specific triggering using anti-Siglec-7 or Siglec-9 antibodies displayed a decreased TNFα secretion by the monocytes, validating the role of the Siglec–Sialic axis in the co-culture experiments. Together, our results demonstrate that glioblastoma cells induce a myeloid immune-suppressive phenotype that could be partly rescued by lowering the glioblastoma-associated sialic acid levels. This manuscript supports further research of the Siglec–Sialic acid axis in the context of glioblastoma and its potential to improve clinical outcome. Full article