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<p>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<sup>+</sup> 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<sup>−</sup>CD8<sup>+</sup> T (CD103N) cells are significantly increased in pMMR CRC tissue compared to adjacent non-tumor tissue. Distinguish from CD103<sup>+</sup>CD8<sup>+</sup> T (CD103P) cells with elevated T<sub>EX</sub> markers, these CD103N cells display a precursor exhausted T cells (T<sub>PEX</sub>) 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<sub>PEX</sub>-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<sub>PEX</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Jinsheng Liu,
  • Jintao Zeng,
  • Ting Zhou,
  • Mi Wu,
  • Xiufang Weng

摘要

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 TEX markers, these CD103N cells display a precursor exhausted T cells (TPEX) 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 TPEX-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 TPEX 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.