Unraveling the Effects and Characteristics of Proliferating Tumor and Cytotoxic T Cells in Colorectal Cancer.

Abstract

The prognostic role of tumor proliferation in colorectal cancer has been unclear, whereas T-cell proliferation has been associated with favorable outcomes. We investigated characteristics and prognostic significance of proliferating tumor and cytotoxic T cells. Two independent colorectal cancer cohorts comprising 1,839 patients were analyzed using multiplex IHC for MKI67 (Ki-67), CD8, and CK. Densities and spatial localization of MKI67+ and MKI67- cytotoxic T cells and tumor proliferation rate were assessed via digital image analysis. Single-cell RNA sequencing data from 62 colon cancers were used to characterize proliferating and nonproliferating cells. High MKI67+ tumor cell percentage was associated with better cancer-specific survival, an antitumorigenic immune microenvironment, downregulation of epithelial-mesenchymal transition, and upregulation of MYC signaling. In the larger cohort, the multivariable HR for high versus low proliferation rate was 0.60 (95% confidence interval, 0.43-0.83). MKI67+CD8+ T cells exhibited high expression of effector molecules such as GZMB and IFNG and stronger association with favorable prognosis than MKI67-CD8+ T cells. The multivariable HR for high versus low MKI67+CD8+ T-cell density was 0.49 (95% confidence interval, 0.35-0.70). However, spatial analysis of tumor cell-T cell co-localization indicated comparable prognostic significance for both subsets when considering their proximity to tumor cells. Tumor cell proliferation is a marker for better prognosis in colorectal cancer. Although proliferating cytotoxic T cells demonstrate stronger prognostic value than nonproliferating cytotoxic T cells, spatial proximity to tumor cells diminishes this difference. These findings provide new insights into the interplay between tumor proliferation, immune response, and patient outcomes in colorectal cancer.