UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Biochim Biophys Acta Rev Cancer. 2020 Dec;1874(2):188447. doi: 10.1016/j.bbcan.2020.188447. Epub 2020 Oct 6.
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 (~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 MSI-H CRCs. Furthermore, we address the potential strategies to sensitize pMMR/MSS CRC to immunotherapy by converting an immunologically "cold" microenvironment into a "hot" one.
错配修复缺陷（dMMR）或微卫星高度不稳定（MSI-H）的结直肠癌（CRC）通常对免疫检查点抑制剂（ICIs）有持续的反应，包括针对程序性死亡受体 1（PD-1）、程序性死亡配体 1（PD-L1）和细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）的选择性单克隆抗体。然而，相当一部分 dMMR CRC 对免疫疗法没有反应或最终产生耐药性。大多数（约 85%）CRC 是错配修复功能完整（pMMR）或微卫星稳定（MSS）的，对 ICIs 没有反应。了解 dMMR 相关免疫原性的生物学和机制对于提高免疫疗法在 CRC 中的治疗效果至关重要。与 pMMR/MSS CRC 相比，dMMR/MSI CRC 通常具有更高的肿瘤突变负担（TMB）、对 5-氟尿嘧啶为基础的化疗的反应率更低、独特的免疫特征，如高肿瘤浸润淋巴细胞（TILs）和更好的预后。在这里，我们综述了 dMMR/MSI 在 CRC 中的临床相关性、用免疫疗法靶向 dMMR CRC 的分子基础和原理，以及使用 ICI 作为单一药物或与其他疗法联合治疗 MSI-H CRC 的临床方法。此外，我们还探讨了通过将免疫“冷”微环境转化为“热”微环境来使 pMMR/MSS CRC 对免疫疗法敏感的潜在策略。
