Sex differences in the colorectal tumor immune microenvironment.

283 Background: Males have increased risk and mortality rates of colorectal cancer (CRC) compared to females, but the reasons for these disparities are not well understood. Immune responses differ by sex, and a robust T cell response is an important prognostic indicator in CRC. We hypothesized that females exhibit a stronger CRC-associated T cell response, contributing to reduced mortality in females compared to males. Methods: The study cohort included 2,751 incident CRC patients (1,337 female; 1,414 male) from a population-based case-control study. T cell receptor (TCR) abundance and clonality were quantified using immunoSEQ, and a gastrointestinal pathologist scored tumor-infiltrating lymphocyte counts per high-powered field (TILs/hpf). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between T cell metrics and sex, adjusting for age, anatomic site, and microsatellite instability (MSI) status. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals for the association between sex and 5-year all-cause and CRC-specific survival, adjusting for known prognostic indicators. We also conducted a formal test for interaction between sex and T cell features in relation to survival outcomes. Results: There were no associations between sex and TCR abundance (OR=1.05, 95% CI=0.98-1.13, p=0.14), TCR clonality (OR=0.99, 95% CI=0.91-1.06, p=0.72), or TILs/hpf (OR=1.05, 95% CI=0.88-1.25, p=0.60). We observed no differences in overall or disease-specific five-year survival between males and females. Further, the associations between T cell responses and survival did not significantly differ by sex. Conclusions: In a well-powered analysis, no robust sex differences were observed in the CRC immune microenvironment or in the relationship between T cell infiltration and CRC outcomes. The high burden of CRC and the emergence of immunotherapy as an important therapeutic approach suggest a need for further research investigating immunological sex differences in the setting of treatment response. Summary of associations between the colorectal tumor T cell response and sex. T cell Features Odds Ratio(Female vs. Male) Lower 95% CI Upper 95% CI P Value TCR Abundance 1.05 0.98 1.13 0.14 TCR Clonality 0.99 0.91 1.06 0.72 TILs/hpf* <2 1.05 0.88 1.25 0.60 *A total of 99 patients (45 female; 54 male) with missing TILs/hpf data were excluded from the regression analysis.