Role of T cell exhaustion and tissue-resident memory T cells in the expression and prognosis of colorectal cancer.

The tumour microenvironment (TME) is complex and dynamic, and changes significantly with tumour progression. Studying the evolving state of T cells, especially tumour-specific subsets, has become feasible. However, the roles of exhausted T cells (Tex) and pre-exhausted tissue-resident memory T cells (pf-Trm), which emerge after prolonged antigen stimulation, remain unclear. Using single-cell sequencing data, we analyzed the immune landscape of patients with colorectal cancer (CRC) across clinical stages to quantify the abundance of T cell subtypes. Functional enrichment analysis revealed that early stage Tex cells retained some functionality, whereas advanced stage Tex cells showed a significant functional loss. Early stage pf-Trm cells actively participate in immune surveillance and antigen presentation, whereas advanced stage pf-Trm cells exhibit reduced functions. Flow cytometry analysis of clinical cohorts was used to measure the proportions of Tex and pf-Trm. Elevated levels of PD-1 and Tim-3 have been detected in TILs from CRC patients. Data from The Cancer Genome Atlas (TCGA) linked high Tex levels to poor prognosis in CRC, while pf-Trm correlated with better outcomes in early CRC but worse outcomes in advanced CRC due to functional exhaustion. Thus, Tex and pf-Trm cells may serve as prognostic biomarkers, and Tim-3 and CD103 may be promising targets for immune checkpoint inhibitors.