TIGIT+ CD4+ T Cell Enrichment in Colorectal Liver Metastases Is Associated with Shorter Survival.

BACKGROUND/OBJECTIVES: The immune microenvironment of colorectal cancer liver metastases (CRCLM) differs from that of primary colorectal tumors and may influence responses to immunotherapy. We aimed to characterize T cell subsets and checkpoint receptor expression in CRCLM and explore associations with overall survival. METHODS: We performed flow cytometric profiling of matched peripheral blood, non-tumor liver tissue, and CRCLM specimens from 17 patients undergoing hepatic metastasectomy. A separate cohort of 19 patients was studied using ex vivo expanded TILs. Kaplan-Meier/log-rank analyses were complemented by Cox models using dichotomized and continuous marker values, median-cut-off and permutation sensitivity analyses, and post hoc clinical covariate comparisons. RESULTS: CRCLM showed relative enrichment of CD4+ T cells and depletion of CD8+ T cells. In the fresh cohort, 16 patients (12 deaths) were evaluable for CRCLM TIGIT+ CD4+ cells. The optimized split was associated with shorter survival for the high group (HR 5.26, 95% CI 1.54-17.94; log-rank p = 0.0036). The median-cut-off analysis showed the same direction (HR 3.17, 95% CI 0.92-11.00; p = 0.0551), as did the continuous model (HR 1.69 per 10-percentage-point increase, 95% CI 0.82-3.45; p = 0.153). In the expanded cohort, the optimized high-versus-low HR was 17.47 (95% CI 3.23-94.59; p < 0.001), and the continuous HR was directionally concordant (HR 2.68, 95% CI 0.96-7.51; p = 0.060). Clinical characteristics were balanced between optimized low and high groups. CONCLUSIONS: TIGIT+ CD4+ T cell enrichment showed an exploratory association with shorter survival in CRCLM and represents a promising candidate for further prognostic and functional investigation. The separate expanded cohort provided complementary evidence supporting this observation.