Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2021 Feb;9(2). doi: 10.1136/jitc-2020-001819.
Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.
To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.
Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting and sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.
Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.
尽管免疫疗法已被广泛应用于多种癌症的治疗，但大多数患者对免疫疗法无反应或在初始反应后复发。这些失败可能归因于肿瘤细胞采用的免疫抑制机制。然而，使用常规方法系统评估肿瘤内在因素作为癌症患者免疫调节剂的潜力具有挑战性。
为了以无偏倚的方式确定癌症免疫治疗无应答者的免疫抑制机制，我们进行了全基因组 CRISPR 免疫筛选，并将我们的结果与多组学临床数据相结合，以评估肿瘤内在因素在调节癌症免疫治疗的两个限速步骤中的作用，即 T 细胞肿瘤浸润和 T 细胞介导的肿瘤杀伤。
我们的研究揭示了两种不同类型的免疫抵抗调节剂，并证明它们具有作为治疗靶点的潜力，可以提高免疫疗法的疗效。其中，PRMT1 和 RIPK1 分别被鉴定为双重免疫抵抗调节剂和细胞毒性抵抗调节剂。尽管不同类型免疫疗法的幅度不同，但基因靶向和敏化肿瘤对 T 细胞杀伤和抗 PD-1/OX40 治疗的敏感性。有趣的是，尽管对 T 细胞肿瘤浸润的影响有限，但 RIPK1 特异性抑制剂增强了基于 T 细胞的和抗 OX40 治疗的抗肿瘤活性。
总的来说，这些数据为合理的免疫肿瘤学联合治疗提供了丰富的新型靶点资源。
