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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.