Tumor Cell Targeting Research Unit, GlaxoSmithKline, Collegeville, Pennsylvania.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Immunol Res. 2022 Apr 1;10(4):420-436. doi: 10.1158/2326-6066.CIR-21-0614.
Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I PRMTs remains uncharacterized. Here, our The Cancer Genome Atlas dataset analysis revealed that expression of type I PRMTs associated with poor clinical response and decreased immune infiltration in patients with melanoma. In cancer cell lines, inhibition of type I PRMTs induced an IFN gene signature, amplified responses to IFN and innate immune signaling, and decreased expression of the immunosuppressive cytokine VEGF. In immunocompetent mouse tumor models, including a model of T-cell exclusion that represents a common mechanism of anti-programmed cell death protein 1 (PD-1) resistance in humans, type I PRMT inhibition increased T-cell infiltration, produced durable responses dependent on CD8+ T cells, and enhanced efficacy of anti-PD-1 therapy. These data indicate that type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade (ICB) to induce durable antitumor responses in a T cell-dependent manner, suggesting that type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.
蛋白精氨酸甲基转移酶（PRMT）是广泛表达的一类酶，负责催化许多蛋白质底物上的精氨酸甲基化。其中，I 型 PRMT 负责生成非对称二甲基精氨酸。通过控制多种基本的细胞过程，如 DNA 损伤反应、转录调控和 mRNA 剪接，I 型 PRMT 促进了癌症的发生和发展。一种 I 型 PRMT 抑制剂 GSK3368715 已被开发出来，并已进入实体瘤和血液恶性肿瘤的临床试验阶段。虽然已经报道 I 型 PRMT 参与调节免疫细胞功能，但肿瘤内源性途径受 I 型 PRMT 调控的免疫作用仍未被阐明。在这里，我们通过癌症基因组图谱数据集分析发现，黑色素瘤患者中 I 型 PRMT 的表达与临床反应不良和免疫浸润减少有关。在癌细胞系中，抑制 I 型 PRMT 诱导 IFN 基因特征，放大 IFN 和先天免疫信号的反应，并降低免疫抑制细胞因子 VEGF 的表达。在免疫功能正常的小鼠肿瘤模型中，包括一种 T 细胞排斥模型，该模型代表了人类抗程序性细胞死亡蛋白 1（PD-1）耐药的常见机制，I 型 PRMT 抑制增加了 T 细胞浸润，产生依赖于 CD8+T 细胞的持久反应，并增强了抗 PD-1 治疗的疗效。这些数据表明，I 型 PRMT 抑制具有免疫调节特性，并与免疫检查点阻断（ICB）协同作用，以 T 细胞依赖性方式诱导持久的抗肿瘤反应，表明 I 型 PRMT 抑制可以增强难治性肿瘤中的抗肿瘤免疫。
