Cancer Immunity and Immunotherapy: Early Detection, Diagnosis, Systemic Treatments, Novel Biomarkers, and Resistance Mechanisms

Background: EGFR and ERBB2 exon 20 insertion (Ex20ins) account for a small fraction of patients with EGFR mutations. The efficacy of immune checkpoint inhibitors (ICIs) for these patients was still controversial. Methods: This retrospective study enrolled lung cancer patients harboring either EGFR or ERBB2 Ex20ins mutations. All the patients were treated with platinum-based chemotherapy plus ICIs, or platinum-based chemotherapy. The demographic features and clinical outcome of each patient were reviewed and analyzed. Results: When treated with immunochemotherapy, patients with EGFR/ERBB2 Ex20ins mutations (n = 31) had poor PFS compared with those without EGFR mutations (n = 141, 5.0 mon and 11.2 mon, p < 0.001). When compared with those with EGFR classic mutations who received immunotherapy as the salvage therapy (n = 24), these patients with EGFR/ERBB2 Ex20ins mutations had similar PFS (5.0 mon and 4.1 mon, p = 0.625), ORR (37.5% vs. 48.4%), and DCR (70.8% vs. 77.4%). In the patients with EGFR/ERBB2 Ex20ins mutations, the PFS of those treated with chemotherapy (n = 54) and those treated with immunochemotherapy (n = 31) was 6.5 mon vs. 5.0 mon (p = 0.066). In the EGFR Ex20ins subgroup, the PFS of addition of bevacizumab to chemotherapy (n = 20) and chemotherapy alone (n = 16) was 8.8 mon and 5.2 mon, respectively (p = 0.082) or immunochemotherapy (n = 15, 8.8 mon and 5.0 mon, p = 0.097). Similarly, in the ERBB2 subgroup, the combination of bevacizumab and chemotherapy achieved a numerically longer PFS over chemotherapy alone (9.1 mon and 4.5 mon, p = 0.253), but there was no statistical significance. Conclusions: This study showed that platinum-based chemotherapy plus ICIs had limited efficiency compared to platinum-based chemotherapy for patients with EGFR/ERBB2 Ex20ins. Chemotherapy plus bevacizumab may be a potential scheme for these patients. Full article

Esophageal cancer is a highly aggressive and deadly disease, ranking as the sixth leading cause of cancer-related deaths worldwide. Despite advances in treatment, the prognosis remains poor. A multidisciplinary approach is crucial for achieving complete remission, with treatment options varying based on disease stage. Surgical intervention and endoscopic treatment are used for localized cancer, while systemic treatments like chemoradiotherapy and targeted drug therapy play a crucial role. Molecular markers such as HER2 and EGFR can be targeted with drugs like trastuzumab and cetuximab, and immunotherapy drugs like pembrolizumab and nivolumab show promise by targeting immune checkpoint proteins. Epigenetic modifications offer new avenues for targeted therapy. Treatment selection depends on factors like stage, tumor location, and patient health, with post-operative and rehabilitation care being essential. Early diagnosis, appropriate treatment, and supportive care are key to improving outcomes. Continued research is needed to develop effective targeted drugs with minimal side effects. This review serves as a valuable resource for clinicians and researchers dedicated to enhancing esophageal cancer treatment outcomes. Full article

Substantial evidence has accumulated showing that psychological distress affects immune regulation, the response to cancer treatment, and survival. The effect of psychological parameters on the effectiveness of immune checkpoint inhibitor (ICI) treatment has not yet been studied. This preliminary study aimed to (a) examine the associations between psychological factors and responses to ICI treatment and (b) assess the associations between psychological factors and blood measures of sPD-1, sCTLA-4, and cytokines that may alter the effect of ICI treatment. The participants were 62 individuals with advanced cancer, aged 18 years or older, who were candidates for ICI treatment as a new line of treatment. The participants answered questionnaires and provided blood samples and medical data prior to the start of ICI treatment and 3 months after. Perceived health status was positively associated with better responses to ICI treatment. In the subsample of participants with biomarkers, worse health-related quality of life was associated with higher IL-6 and sCTLA-4; emotional distress and sleep difficulties were associated with higher sCTLA-4; and better perceived health was associated with lower IL-6 and TNFα. sPD-1 was not associated with psychological measures. This preliminary study found for the first time that some psychological measures could be linked to responses to cancer treatment, possibly via pro-inflammatory cytokines and sCTLA-4. Full article

Background: The majority of melanoma is diagnosed in individuals between 55 and 84 years old. Current data varied in reporting differences in survival outcomes amongst different age groups. Methods: A retrospective, multi-center, provincial cohort database was used to investigate the relationship between age (<65 or ≥65 years old) and overall survival. Patients must have had histologically confirmed locally advanced or metastatic melanoma and had to have received at least one cycle of immunotherapy (single agent nivolumab, pembrolizumab, or combination ipilimumab plus nivolumab). Results: From August 2013 to May 2020, we identified 497 patients (median age = 64 [range 12–96 years]; 65.2% men; 36.4% with a BRAF mutation (V600E and V600K)). Of these, 260 were < 65 years old, and 237 were ≥65 years old. A total of 39.1% of the patients in the younger cohort received combination ICI compared with 10.2% in the older cohort, and the difference was statistically significant. Median survival amongst individuals aged ≥65 years old was shorter compared to individuals <65 years old, with a median overall survival of 17.1 (95% CI 12.3–22.9 months) months and 22.2 months (95% CI 18.7–33.8 months), respectively (p = 0.04), at a median follow-up of 34.4 months (range: 1.84–81.4 months). The survival difference was present in the cutaneous melanoma cohort where median OS was 18.2 months (95% CI 12.3–30.4 months) in patients ≥65 years old and 23.8 months (95% CI 19.2–48.2 months) in patients <65 years old, p = 0.04. There were no significant differences by age in the non-cutaneous melanoma cohort. A combination of nivolumab plus ipilimumab was associated with an improved overall survival hazard ratio of 0.48 (95% CI 0.36–0.65) as compared to anti-PD-1 monotherapy alone (p < 0.001). In the cutaneous cohort treated with anti-PD-1 monotherapy (n = 306), no significant differences were seen with median OS at 16.1 months (95% CI 11.4–25.7 months) in patients ≥65 years old and 17.1 months (95% CI 12.0–22.2 months) in patients <65 years old (p = 0.84). Tumor response to anti-PD-1 was higher in the older patients compared with the response in younger patients with cutaneous melanoma. Conclusions: Older melanoma patients have similar survival compared with younger patients after receiving the same treatment with anti-PD-1 monotherapy. The superior survival observed in the younger patients is possibly related to the higher utilization of combination ICI. Tumor response to immunotherapy is superior in older patients with cutaneous melanoma; however, younger patients may improve their survival by using combination ICI. Full article

With the rise of novel immunotherapies able to stimulate the antitumor immune response, increasing literature concerning the immunogenicity of breast cancer has been published in recent years. Numerous clinical studies have been conducted in order to identify novel biomarkers that could reflect the immunogenicity of BC and predict response to immunotherapy. In this regard, TILs have emerged as an important immunological biomarker related to the antitumor immune response in BC. TILs are more frequently observed in triple-negative breast cancer and HER2+ subtypes, where increased TIL levels have been linked to a better response to neoadjuvant chemotherapy and improved survival. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in breast cancer is observed in about 10–30% of cases and is extremely variable based on tumor stage and molecular subtypes. Briefly, TNBC shows the highest percentage of PD-L1 positivity, followed by HER2+ tumors. On the other hand, PD-L1 is rarely expressed (0–10% of cases) in hormone-receptor-positive BC. The prognostic role of PD-L1 expression in BC is still controversial since different immunohistochemistry (IHC) clones, cut-off points, and scoring systems have been utilized across published studies. In the present paper, an extensive review of the current knowledge of the immune landscape of BC is provided. TILS and PD-L1 expression across different BC subtypes are discussed, providing a guide for their pathological assessment and reporting. Full article

Background: The mechanism by which infiltrating CD8+ T lymphocytes in the tumour microenvironment influence the survival of patients with ovarian cancer (OC) remains unclear. Methods: To identify biomarkers to optimise OC treatment, 13 immune-cell-line-associated datasets, RNA sequencing data, and clinical data from the GEO, TCGA, and the ICGC were collected. Gene expression in OC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining. Results: We identified 520 genes and three immunological clusters (IC1, IC2, and IC3) associated with CD8+ T cells. Higher IFN scores, immune T cell lytic activity, and immune cell infiltration and upregulated expression of immune-checkpoint-related genes indicated that IC3 is more responsive to immunotherapy, whereas IC1 and IC2 have a poorer prognosis. A 10-gene signature, including SEMA4F, CX3CR1, STX7, PASK, AKIRIN2, HEMGN, GBP5, NSG1, and CXorf65, was constructed, and a multivariate Cox regression analysis revealed a significant association between the 10-gene signature-based risk model and overall survival (p < 0.001). A nomogram was constructed with age and the 10-gene signature. Consistent with the bioinformatics analysis, IHC and qRT-PCR confirmed the accuracy of the signatures in OC tissue samples. The predictive ability of the risk model was demonstrated using the Imvigor210 immunotherapy dataset. Conclusions: The development of a novel gene signature associated with CD8+ T cells could facilitate more accurate prognostics and prediction of the immunotherapeutic response of patients with OC. Full article

Purpose: The immune responses of natural killer (NK) cells against cancer cells vary by patient. Killer Ig-like receptors (KIRs), which are some of the major receptors involved in regulating NK cell activity for killing cancer cells, have significant genetic variation. Numerous studies have suggested a potential association between the genetic variation of KIR genes and the risk of development or prognosis of various cancer types. However, an association between genetic variations of KIR genes and glioblastoma (GB) remains uncertain. We sought to evaluate the association of genetic variations of KIRs and their ligand genes with the risk of GB development in Koreans. Methods: A case–control study was performed to identify the odds ratios (ORs) of KIR genes and Classes A, B, and, C of the human leukocyte antigen (HLA) for GB. The GB group was comprised of 77 patients with newly diagnosed IDH-wildtype GB at our institution, and the control group consisted of 200 healthy Korean volunteers. Results: There was no significant difference in the frequency of KIR genes and KIR haplotypes between the GB and control groups. Genetic variations of KIR-2DL1, 3DL1, and 3DS1 with their ligand genes (HLA-C2, HLA-Bw4/6, and Bw4, respectively) had effects on the risk of GB in Korean patients. The frequency of KIR-2DL1 with HLA-C2 (OR 2.05, CI 1.19–3.52, p = 0.009), the frequency of KIR-3DL1 without HLA-Bw4 (80I) (OR 8.36, CI 4.06–17.18, p < 0.001), and the frequency of KIR-3DL1 with Bw6 (OR 4.54, CI 2.55–8.09, p < 0.001) in the GB group were higher than in the control group. In addition, the frequency of KIR-2DL1 without HLA-C2 (OR 0.44, CI 0.26–0.75, p = 0.003), the frequency of KIR-3DL1 with HLA-Bw4 (80T) (OR 0.13, CI 0.06–0.27, p < 0.001), the frequency of KIR-3DL1 without Bw6 (OR 0.27, CI 0.15–0.49, p < 0.001), and the frequency of KIR-3DS1 with Bw4 (80I) (OR 0.03, CI 0.00–0.50, p < 0.001) in the GB group were lower than in the control group. Conclusions: This study suggests that genetic variations of KIRs and their ligand genes may affect GB development in the Korean population. Further investigations are needed to demonstrate the different immune responses for GB cells according to genetic variations of KIR genes and their ligand genes. Full article

Background: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. Patients and methods: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. Results: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1–2 AEs in 14 patients (16%) and 10 grade 3–4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). Conclusion: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option. Full article

Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up CT. Associations between the baseline variables and progressive disease (PD) were tested by logistic regression analyses. The results showed 46/138 patients had PD. The baseline CT “number of involved organs” by metastasis and smoking pack years were independently associated with PD (p < 0.05), and the ROC analysis showed a good performance of the model that integrated these variables in predicting PD (AUC: 0.79). This pilot study suggests that the combination of baseline CT disease and smoking PY can identify who may progress on pembrolizumab monotherapy and can potentially facilitate decision-making for the optimal first-line treatment in the high PD-L1 cohort. Full article

Background: Survivin is an inhibitor of apoptosis protein (IAP), encoded by the Baculoviral IAP Repeat Containing 5 (BIRC5) gene located on q arm (25.3) on chromosome 17. It is expressed in various human cancers and involved in tumor resistance to radiation and chemotherapy. The genetic analysis of the BIRC5 gene and its protein survivin levels in buccal tissue related to oral squamous cell carcinoma (OSCC) in South Indian tobacco chewers has not been studied. Hence, the study was designed to quantify survivin in buccal tissue and its association with pretreatment hematological parameters and to analyze the BIRC5 gene sequence. Method: In a single centric case control study, buccal tissue survivin levels were measured by ELISA. A total of 189 study subjects were categorized into Group 1 (n = 63) habitual tobacco chewers with OSCC, Group 2 (n = 63) habitual tobacco chewers without OSCC, and Group 3 (n = 63) healthy subjects as control. Retrospective hematological data were collected from Group 1 subjects and statistically analyzed. The BIRC5 gene was sequenced and data were analyzed using a bioinformatics tool. Results: Survivin protein mean ± SD in Group 1 was (1670.9 ± 796.21 pg/mL), in Group 2 it was (1096.02 ± 346.17 pg/mL), and in Group 3 it was (397.5 ± 96.1 pg/mL) with significance (p < 0.001). Survivin levels showed significance with cut-off levels of absolute monocyte count (AMC), neutrophil/lymphocyte ratio (NLR), and lymphocyte/monocyte ratio (LMR) at (p = 0.001). The unique variants found only in OSCC patients were T → G in the promoter region, G → C in exon 3, C → A, A → G, G → T, T → G, A → C, G → A in exon 4, C → A, G → T, G → C in the exon 5 region. Conclusions: The tissue survivin level increased in OSCC patients compared to controls; pretreatment AMC, LMR, and NLR may serve as add-on markers along with survivin to measure the progression of OSCC. Unique mutations in the promoter and exons 3–5 were observed in sequence analysis and were associated with survivin concentrations. Full article

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM. Full article

The burden of hepatocellular carcinoma (HCC) is on the rise in the Gulf region, with most patients being diagnosed in the intermediate or advanced stages. Surgery is a treatment option for only a few, and the majority of patients receive either locoregional treatment (percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization [TACE], radioembolization, radiotherapy, or transarterial radioembolization) or systemic therapy (for those ineligible for locoregional treatments or who do not benefit from TACE). The recent emergence of novel immunotherapies such as immune checkpoint inhibitors has begun to change the landscape of systemic HCC treatment in the Gulf. The combination of atezolizumab and bevacizumab is currently the preferred first-line therapy in patients not at risk of bleeding. Additionally, the HIMALAYA trial has demonstrated the superiority of the durvalumab plus tremelimumab combination (STRIDE regimen) therapy in efficacy and safety compared with sorafenib in patients with unresectable HCC. However, there is a lack of data on post-progression treatment after first-line therapy with either atezolizumab plus bevacizumab or durvalumab plus tremelimumab regimens, highlighting the need for better-designed studies for improved management of patients with unresectable HCC in the Gulf region. Full article

The aim of our study was to determine the potential role of CT-based radiomics in predicting treatment response and survival in patients with advanced NSCLC treated with immune checkpoint inhibitors. We retrospectively included 188 patients with NSCLC treated with PD-1/PD-L1 inhibitors from two independent centers. Radiomics analysis was performed on pre-treatment contrast-enhanced CT. A delta-radiomics analysis was also conducted on a subset of 160 patients who underwent a follow-up contrast-enhanced CT after 2 to 4 treatment cycles. Linear and random forest (RF) models were tested to predict response at 6 months and overall survival. Models based on clinical parameters only and combined clinical and radiomics models were also tested and compared to the radiomics and delta-radiomics models. The RF delta-radiomics model showed the best performance for response prediction with an AUC of 0.8 (95% CI: 0.65−0.95) on the external test dataset. The Cox regression delta-radiomics model was the most accurate at predicting survival with a concordance index of 0.68 (95% CI: 0.56−0.80) (p = 0.02). The baseline CT radiomics signatures did not show any significant results for treatment response prediction or survival. In conclusion, our results demonstrated the ability of a CT-based delta-radiomics signature to identify early on patients with NSCLC who were more likely to benefit from immunotherapy. Full article

The presence of CD169⁺ macrophages in the draining lymph nodes of cancer patients is, for unknown reasons, associated with a beneficial prognosis. We here investigated the prognostic impact of tumor-infiltrating CD169⁺ macrophages in primary tumors (PTs) and their spatial relation to tumor-infiltrating B and T cells. Using two breast cancer patient cohorts, we show that CD169⁺ macrophages were spatially associated with the presence of B and T cell tertiary lymphoid-like structures (TLLSs) in both PTs and lymph node metastases (LNMs). While co-infiltration of CD169⁺/TLLS in PTs correlated with a worse prognosis, the opposite was found when present in LNMs. RNA sequencing of breast tumors further confirmed that SIGLEC1 (CD169) expression was associated with mature tertiary lymphoid structure (TLS), and T_reg and B_reg signatures. We propose that the negative prognostic value related to CD169⁺ macrophages in PTs is a consequence of an immunosuppressive tumor environment rich in TLSs, T_regs and B_regs. Full article