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首页> 外文期刊>Biochimica et biophysica acta. Reviews on cancer >Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside
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Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside

机译：免疫疗法对不匹配修复缺陷性结直肠癌的疗效：从长凳到床边

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Colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) often have sustained responses to immune checkpoint inhibitors (ICIs) including selective monoclonal antibodies against Program Death 1 (PD-1), Programmed Death Ligand 1(PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4). However, a substantial fraction of dMMR CRCs do not respond or ultimately develop resistance to immunotherapy. The majority (similar to 85%) of CRCs are MMR proficient (pMMR) or microsatellite stable (MSS) and lack response to ICIs. Understanding the biology and mechanisms underlying dMMR-associated immunogenicity is urgently needed for improving the therapeutic efficacy of immunotherapy on CRC. Compared to pMMR/MSS CRCs, dMMR/MSI CRCs typically have increased tumor mutational burden (TMB), lower response rate to 5-fluorouracil-based chemotherapy, distinctive immunological features such as high tumor-infiltrating lymphocytes (TILs), and better prognosis. Here, we review the current understanding of the clinical relevance of dMMR/MSI in CRCs, the molecular basis and rationales for targeting dMMR CRC with immunotherapy, and clinical approaches using ICIs as single agents or in combination with other therapies for MSIH CRCs. Furthermore, we address the potential strategies to sensitize pMMR/MSS CRC to immunotherapy by converting an immunologically "cold" microenvironment into a "hot" one.
机译：具有缺陷术修复（DMMR）或微卫星不稳定 - 高（MSI-H）的结肠直肠癌（CRC）通常对免疫检查点抑制剂（ICIS）的持续反应，包括针对程序死亡1（PD-1），编程死亡配体的选择性单克隆抗体1（PD-L1）和细胞毒性T淋巴细胞相关抗原4（CTLA-4）。然而，大部分DMMR CRC不会响应或最终产生对免疫疗法的抵抗力。大多数（类似于85％）的CRC是MMR精通（PMMR）或微卫星稳定（MSS），缺乏对ICIS的反应。理解DMMR相关免疫原性基础的生物学和机制是迫切需要改善免疫疗法对CRC的治疗效果。与PMMR / MSS CRC相比，DMMR / MSI CRCs通常具有增加的肿瘤突变负荷（TMB），对5-氟尿基化疗的较低反应速率，诸如高肿瘤浸润性淋巴细胞（TILS）的独特免疫功能，以及更好的预后。在这里，我们审查目前对DMMR / MSI在CRC中的临床相关性，分子基础和用于靶向DMMR CRC的临床相关性，用于靶向DMMR CRC与免疫疗法，以及使用ICIS作为单一药剂的临床方法或与MSIH CRC的其他疗法组合。此外，我们通过将免疫系统“冷”微环境转化为“热”，解决潜在的策略来解决PMMR / MSS CRC对免疫疗法的潜在策略。

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