Mutation of neurotrophic tyrosine receptor kinase can promote pan-cancer immunity and the efficacy of immunotherapy.

The Neurotrophic tyrosine receptor kinase (NTRK) family plays important roles in tumor progression and is involved in tumor immunogenicity. Here, we conducted a comprehensive bioinformatic and clinical analysis to investigate the characteristics of NTRK mutations and their association with the outcomes in pan-cancer immunotherapy. In 3888 patients across 12 cancer types, patients with NTRK-mutant tumors showed more benefit from immunotherapy in terms of objective response rate (ORR; 41.7% vs. 27.5%; P < 0.001), progress-free survival (PFS; HR = 0.80; 95% CI, 0.68-0.96; P = 0.01), and overall survival (OS; HR = 0.71; 95% CI, 0.61-0.82; P < 0.001). We further constructed and validated a nomogram to estimate survival probabilities after the initiation of immunotherapy. Multi-omics analysis on intrinsic and extrinsic immune landscapes indicated that NTRK mutation was associated with enhanced tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses. In summary, NTRK mutation may promote cancer immunity and indicate favorable outcomes in immunotherapy. Our results have implications for treatment decision-making and developing immunotherapy for personalized care.

Sex disparities revealed by single-cell and bulk sequencing and their impacts on the efficacy of immunotherapy in esophageal cancer.

BACKGROUND: There is an ongoing debate on whether sex affects immune-suppressive tumor microenvironment and immunotherapy. Here, we explored the underlying molecular bases for sex dimorphisms and their impact on the efficacy of immunotherapy in esophageal cancer (EC). METHODS: 2360 EC patients from phase 3 trials were pooled to compare overall survivals by calculating hazard ratios (HRs) and their 95% confidence intervals (CIs). Genomic data of 1425 samples were integrated to depict the genomic landscapes and antigenic features. We also examined the sex disparities based on single-cell RNA sequencing and T cell receptor-sequencing data from 105,145 immune cells in 60 patients. RESULTS: Immunotherapy was associated with favorable outcomes in men (HR, 0.71; 95% CI, 0.65-0.79; P < 0.001), but not in women (HR, 0.98; 95% CI, 0.78-1.23; P = 0.84) (Pinteraction =0.02). The frequencies of 8 gene mutations, 12 single base substitutions signatures, and 131 reactome pathways were significantly different between male and female. Additionally, six subtypes of HLA-II antigens were enriched in women. Hence, we constructed and then validated a sex-related signature to better predict the outcomes of immunotherapy. Exhausted CD8+ T cells were highly infiltrated in men, while naïve CD8+ T cells were more common in women. Further examinations on multiple malignancies suggested exhausted CD8+ T cells were enriched in patients who responded to immunotherapy. CONCLUSIONS: Our study delineated the robust genomic and cellular sex disparities in EC. Furthermore, male, rather than female, derived significantly benefits from immunotherapy. These results have implications for treatment decision-making and developing immunotherapy for personalized care. In the past several years, immunotherapy has gradually replaced the traditional chemotherapy as the standard treatment in esophageal cancer. It is well-established that immunological responses in male and female differ significantly. However, there is an ongoing debate on whether sex can impact the treatment outcomes in immunotherapy. In the present study, we systematically characterized the genomic and cellular landscapes of esophageal cancer, and revealed the significant differences between male and female patients. Furthermore, with over 2000 patients with esophageal cancer, we showed that only men can benefit from immunotherapy. In women, immunotherapy failed to show superior over chemotherapy. These results have implications for treatment decision-making and developing next-generation immunotherapy for personalized care.

Global burden, risk factors, clinicopathological characteristics, molecular biomarkers and outcomes of microsatellite instability-high gastric cancer.

Microsatellite instability-high (MSI-H) has gained considerable interests since it was approved as a tumor-agnostic biomarker in immunotherapy. However, the reported characteristics of MSI-H gastric cancer (GC) are inconsistent due to the biological complexity. Here, we aim to clarify the prevalence, risk factors, clinicopathological/molecular features and outcomes of MSI-H GC though a comprehensive review on 43246 patients from 134 cohorts. Overall, the proportion of MSI-H GC was 14.5% (95% CI, 13.3%-15.8%). Patients with MSI-H GC were less likely to have Epstein-Barr virus infection. High incidences of MSI-H GC were associated with female, older age, lower gastric body, Lauren intestinal histology, WHO tubular and mucinous subtypes, and early disease stage. Additionally, patients with MSI-H GC harbored more KRAS mutation, PD-L1 positivity, CD8 overexpression, and higher TMB, but less HER2 positivity and TP53 mutation. When treated with conventional strategy, the 5-year survival rates in MSI-H patients (70.3%) and MSI-L/MSS patients (43.7%) were significantly different (p<0.001). Patients with MSI-H GC derived larger benefit from immunotherapy in term of overall survival (pInteraction<0.001) and objective response (pInteraction=0.02). Since the prevalence of MSI-H GC is relatively high and associated with distinct clinicopathological and molecular characteristics, MSI testing should be conducted during standard diagnostical activity. Moreover, giving MSI-H tumors are often diagnosed at early stage and have favorable outcomes, less aggressive treatment strategies may be considered in clinical practice. In summary, this panoramic review may assist in design and/or interpretation of clinical trials, provide references in drug development, and constitute complementary information in drafting the clinical practice guideline.