Sex Differences in Colorectal Tumor-Associated T-cell Responses

Although males exhibit higher colorectal cancer incidence and mortality rates than females, the underlying mechanisms remain unclear. We hypothesized that females mount stronger antitumor T-cell responses, contributing to their improved survival.

Tumor samples from a discovery cohort (Molecular Epidemiology of Colorectal Cancer, N = 2,750) and an independent replication cohort (Spanish study, N = 444) underwent immunosequencing to quantify T-cell receptor (TCR) abundance and clonality. Tumor-infiltrating lymphocytes per high-powered field (TIL/hpf) were also scored in the discovery cohort. Multivariable logistic regression estimated odds ratios (OR) for the associations between sex and T-cell metrics. The data were then stratified by sex, and multivariable Cox proportional hazards regression estimated hazard ratios (HR) for the associations between T-cell metrics and 5-year overall and colorectal cancer-specific survival, adjusting for known prognostic indicators.

Multivariable analysis demonstrated no association between sex and TCR abundance, clonality, or TILs/hpf (P > 0.05 for all) in both discovery and replication cohorts. In multivariable survival analysis, higher TCR abundance and TILs/hpf were consistently associated with improved survival across sexes in both cohorts. TCR clonality showed inconsistent associations across cohorts and sexes. Importantly, formal interaction testing showed no significant interaction between sex and T-cell metrics in relation to survival outcomes for both cohorts.

We observed no significant sex differences in colorectal cancer-associated T-cell responses and no significant interaction between sex and T-cell responses in relation to survival.

Sex differences in colorectal cancer are unlikely to be explained by the differences in the robustness and diversity of tumor-associated T-cell responses.