Density of T-cell Subsets in Colorectal Cancer in Relation to Disease-Specific Survival

Abstract Background: Prior studies have demonstrated that the overall density of T cells in colorectal tumors is favorably associated with colorectal cancer survival; however, few studies have considered the potentially distinct roles of heterogeneous T-cell subsets in different tissue regions in relation to colorectal cancer outcomes. Methods: Including 1,113 colorectal cancer tumors from three observational studies, we conducted in situ T-cell profiling using a customized nine-plex [CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT (keratin), MKI67 (Ki-67), and DAPI] multispectral immunofluorescence assay. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the associations of T-cell subset densities in both epithelial and stromal tissue areas in colorectal cancer with disease-specific survival. Results: Higher CD3+CD4+ and CD3+CD8+ naïve, memory, and regulatory T-cell densities were significantly associated with better colorectal cancer–specific survival in both epithelial and stromal tissue areas (HR highest quantile vs. lowest quantile ranging 0.41–0.68). These associations persisted in models further adjusted for stage at diagnosis and were largely consistent when stratified by microsatellite instability status. However, the further stratification into CD4+ or CD8+ T-cell subsets beyond CD3+ subsets did not significantly improve the performance of our model in explaining colorectal cancer prognosis. Conclusions: The density of T cells in colorectal cancer tissue, both overall and for several T-cell subset populations, is significantly associated with colorectal cancer–specific survival independent of microsatellite instability status and stage at diagnosis. Impact: Higher levels of T-cell densities in different locations with different functions are associated with better colorectal cancer–specific survival.