Precursor exhausted CD8⁺T cells in colorectal cancer tissues associated with patient's survival and immunotherapy...

Exhausted CD8⁺T cells represent a distinct cellular lineage that emerges during both chronic infections and cancers. Recent studies have shown that persistent antigen exposure can drive the differentiation of precursor exhausted CD8⁺T cells, termed T_pex cells, which are characterized as TCF-1⁺PD-1⁺CD8⁺T cells. Elevated T_pex cell frequencies in the tumor microenvironment (TME) are associated with improved overall survival (OS) in cancer patients and heightened responsiveness to anti-PD-1 therapy. In our present study, we utilized multi-color immunohistochemistry (mIHC) to determine the localization and clinical implications of tumor-infiltrating T_pex cells within the TME of human colorectal cancer (CRC) tissues. We also conducted a multi-omics integrative analysis using single-cell RNA sequencing (scRNA-seq) data derived from both the murine MC38 tumor model and human CRC tissues. This analysis helped delineate the transcriptional and functional attributes of T_pex cells within the CRC TME. Furthermore, we employed spatial transcriptome sequencing data from CRC patients to investigate the interactions between T_pex cells and other immune cell subsets within the TME. In conclusion, our study not only established a method for T_pex cell detection using mIHC technology but also confirmed that assessing T_pex cells within the CRC TME could be indicative of patients' survival. We further uncovered the transcriptional and functional characteristics of T_pex cells in the TME and ascertained their pivotal role in the efficacy of immunotherapy against CRC.