Comprehensive Characterization of Tumor Microenvironment Differences in Cancer between Male and Female Patients

Abstract

Background: Sex has been recognized as a key variable that affects cancer initiation, progression, response to therapy, and prognosis outcome. The sex differences of the tumor microenvironment (TME) characterization associated with cancer immunotherapy remains poorly understood. A comprehensive analysis to investigate sex-biased TME related features across a broad range of cancer types is required. Methods: We collected 19 cancer types from The Cancer Genome Atlas (TCGA), and remained 1,771 male and 1,137 female samples with immune infiltration. The sex-based differences of TME related features, including tumor mutational burden (TMB), immune scores, stromal scores, tumor purity, immune cells, immune checkpoint genes, and functional pathways were evaluated in pan-cancer and individual cancer types. Findings: We discovered that male patients possess higher tumor mutational burden (TMB) and tumor purity, but lower immune and stromal scores than female patients in pan-cancer. We then revealed that lung adenocarcinoma, lung squamous carcinoma, kidney papillary carcinoma, and head and neck squamous carcinoma possess significant sex bias in immune cells, immune checkpoint genes, and functional pathways. We further identified male- and female-specific prognostic biomarkers based on immune cells in male and female patients of lung adenocarcinoma and validated our results in two independent datasets. Interpretation: This study provides a comprehensive perspective of sex differences for TME related features in diverse cancers and suggests sex may affect the tumor microenvironment, and which should be considered in cancer immunotherapy. Funding: This work was supported by National Natural Science Foundation of China and Natural Science Foundation of Heilongjiang. Declaration of Interest: None to declare.