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Abstract：
Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.
摘要：
免疫检查点抑制剂（ICI）在转移性结直肠癌（mCRC）患者中的活性和功效方面显示出令人印象深刻的结果，这些患者患有错配修复不足（dMMR）或微卫星不稳定性高（MSI-H）的肿瘤。尽管微卫星状态是ICI疗效的主要预测生物标志物，由于原发性耐药,一定比例的dMMR/MSI-HmCRC肿瘤不能从免疫治疗中获益.对调节dMMR/MSI-HCRC肿瘤和免疫反应的生物学机制的更深入了解可能有助于发现ICIs益处的新的预测性生物标志物，并调整免疫疗法的使用，即使在dMMR/MSI-HmCRC患者中也是如此。此外，几个问题仍然悬而未决，例如dMMR/MSI-HmCRC患者的转移的二次切除和ICIs治疗的最佳持续时间。超越微卫星状态，从未来的角度来看，几种工具(即，已经研究了肿瘤突变负担和PD-L1表达）以阐明其作为预测性生物标志物的可能作用。此外，具有校正域POLE突变的pMMR/MSSCRC肿瘤的一个小亚组的特征是超突变表型,并且可能受益于免疫检查点抑制.在目前的工作中,我们的目的是回顾关于在mCRC中使用ICIs治疗的最新文献，重点关注dMMR/MSI-H和CRC患者的特殊亚组。因此，我们总结了未来可能的目标和最有希望的预测生物标志物。
