Corrò Claudia, Dutoit Valérie, Koessler Thibaud
Translational Research Center in Onco-Hematology, Department of Medicine, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland.
Swiss Cancer Center Léman, 1005 Lausanne, Switzerland.
Cancers (Basel). 2021 Mar 18;13(6):1374. doi: 10.3390/cancers13061374.
Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.
直肠癌在基因和分子水平上是一种异质性疾病，这两个方面对肿瘤免疫微环境都有重大影响。虽然微卫星状态和肿瘤突变负荷与免疫治疗反应相关，但肿瘤浸润淋巴细胞的存在是最有力的预后和预测生物标志物之一。然而，大多数直肠癌的特征是微卫星稳定、肿瘤突变负担低和T细胞浸润差。因此，这些肿瘤对免疫治疗无反应，治疗主要依赖单独放疗或联合化疗，随后进行根治性手术。重要的是，临床前和临床研究表明，放疗可诱导肿瘤微环境的完全重编程，可能使其对免疫检查点抑制敏感。尽管如此，越来越多的证据表明，这种协同效应很大程度上取决于放疗剂量、分割方式和时机。尽管正在进行相关研究，但关于与检查点阻断联合使用时产生最佳临床结果所需的放疗方案的信息仍然非常有限。在这篇综述中，我们描述了直肠癌的分子和免疫异质性，并概述了其预后价值。此外，我们讨论了放疗对肿瘤微环境的影响，重点关注其与免疫检查点抑制剂联合使用的机制和益处。
