Increased CD103^-CD8⁺ TILs with TPEX phenotype replenish anti-tumor T cell pool in mismatch repair-proficient CRC

While mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit strong immunogenicity and better response to immune checkpoint inhibitors, the more prevalent mismatch repair-proficient (pMMR) CRCs typically show poor T- cell infiltration and inferior outcomes. Profiling the limited tumor-infiltrating CD8⁺ T cells helps identify responders and guides new strategies to enhance their infiltration and function in pMMR CRC tumors. Our study reveals that the proportion and number of CD103^-CD8⁺ T (CD103N) cells are significantly increased in pMMR CRC tissue compared to adjacent non-tumor tissue. Distinguish from CD103⁺CD8⁺ T (CD103P) cells with elevated T_EX markers, these CD103N cells display a precursor exhausted T cells (T_PEX) phenotype with elevated stemness properties, reduced exhaustion markers, and retained functional capacity to secrete anti-tumor mediators. Moreover, CD103N cells in pMMR CRC shared a substantial number of identical TCR clonotypes with both CD103P cells in tumor and CD103N cell in peripheral blood. In dMMR CRC patients, enrichment of T_PEX-like CD103N cells is associated with a favorable prognosis following anti-PD-1 therapy, suggesting their association with clinical outcome. Our findings identify an expanded population of CD103N cells exhibiting a T_PEX phenotype with anti-tumor potential in pMMR CRC, highlighting their promise as therapeutic targets for recruitment into the tumor microenvironment to enhance the efficacy of immunotherapy.