The sex-based profiles of molecular biomarkers for immunotherapy responses of cancer patients

Abstract Background Published clinical trials have yielded controversial findings regarding the effects of sex on the benefits of immune checkpoint inhibitors (ICIs). Sex-associated differences in the efficacy of immunotherapy remain an important, unresolved question. Methods We investigated sex-biased molecular profiles across a multitude of biomarkers linked to immunotherapy responses. Multiomics data from major solid tumors in The Cancer Genome Atlas, with sufficient sample sizes (≥50 patients of each sex), were analyzed. Ninety-five molecular markers characterizing 4 distinct aspects of the tumor immune system were summarized and compared. The inverse probability of weights algorithm was used to generate well-balanced sex subgroups. Results Our results showed that lung squamous cell carcinoma (LUSC), pancreatic adenocarcinoma, and liver hepatocellular carcinoma were the top 3 cancer types with extensive sex-biased biomarker profiles (31/95, 15/95, and 14/95, respectively). Notably, although both were categorized as non–small cell lung carcinoma, LUSC harbored significantly more sex-biased immunological features than those of lung adenocarcinoma ( p < 0.01). We further explored the validity of this finding by analyzing ICI-responsive signatures and individual patient-level data for non–small cell lung carcinoma and found that sex had significant interaction effects on immunotherapy outcomes in LUSC ( p interaction < 0.05), with women tending to derive greater benefits from ICIs than men. However, this difference was not apparent in the lung adenocarcinoma group ( p interaction = 0.66), with men and women deriving comparable benefits. Conclusions We systematically characterized sex-biased profiles of key molecular biomarkers predicting immunotherapy responses across solid tumors, which could pave the way for individualized therapeutic approaches for men and women.