Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Semin Cancer Biol. 2018 Oct;52(Pt 2):189-197. doi: 10.1016/j.semcancer.2018.02.010. Epub 2018 Mar 1.
Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker-guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application.
结直肠癌（CRC）是一种常见且致命的疾病，具有很高的治疗需求。对于大多数转移性 CRC 患者，化疗是唯一可行的选择。目前，免疫疗法仅限于错配修复缺陷（dMMR/MSI）CRC 的特定遗传亚组。抗 PD1 疗法最近被 FDA 批准作为该亚组的二线治疗。然而，在转移性环境中，这些 dMMR/MSI 肿瘤在数量上远远超过错配修复正常（pMMR/MSS）肿瘤。这些 pMMR/MSS 肿瘤对任何传统的免疫疗法都没有明显的反应，包括检查点阻断、过继细胞转移和疫苗接种。这种对免疫疗法的抵抗是由于复杂的肿瘤微环境通过组合抗原性差的肿瘤细胞和免疫抑制性肿瘤微环境来对抗抗肿瘤免疫。为了找到克服大多数 CRC 患者免疫疗法耐药的方法，有必要深入分析肿瘤遗传学背景下肿瘤免疫组成的个性化方式。需要灵活的、基于生物标志物的早期免疫疗法试验来优化这一工作流程。在这篇综述中，我们详细介绍了 CRC 中免疫逃逸的关键机制和新兴的免疫生物标志物，用于个性化免疫治疗。此外，我们还提出了一个基于生物标志物的临床试验模板，以推动新的免疫疗法更接近临床应用。
