MTA-合作型 PRMT5 抑制剂增强了 MTAP 缺失肿瘤中的 T 细胞介导的抗肿瘤活性。
MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors.
机构信息
Biology and Biochemistry, University of Houston, Houston, Texas, USA.
Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
出版信息
J Immunother Cancer. 2024 Sep 23;12(9):e009600. doi: 10.1136/jitc-2024-009600.
BACKGROUND
Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer.
METHODS
Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells and . Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor.
RESULTS
GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors.
CONCLUSION
Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.
背景
高活性蛋白精氨酸甲基转移酶（PRMTs）与人类癌症有关。据报道，抑制肿瘤内在的 PRMT5 可以增强抗肿瘤免疫反应，这突显了将 PRMT5 抑制剂（PRMT5i）与癌症免疫疗法相结合的可能性。然而，PRMT5 活性的全面抑制会损害免疫细胞的效应功能。在这里，我们试图寻找专门抑制肿瘤组织中 PRMT5 活性的策略，并开发有效的基于 PRMT5i 的免疫肿瘤学（IO）组合来治疗癌症，特别是治疗甲基硫腺苷磷酸化酶（MTAP）缺失的癌症。
方法
通过 CRISPR/Cas9 敲除生成了具有和不具有 MTAP 缺失的同基因肿瘤系。在这些同基因肿瘤系和 T 细胞中评估了两种 PRMT5 抑制剂（GSK3326595 和 MRTX1719）的效果。对肿瘤和 T 细胞对 PRMT5i 治疗的转录组和蛋白质组变化进行了表征。此外，在具有 MTAP 缺失肿瘤的两种同种异体小鼠模型中评估了 MRTX1719 与免疫检查点阻断的联合疗效。
结果
GSK3326595 可显著抑制肿瘤和 T 细胞中的 PRMT5 活性，而与 MTAP 状态无关。然而，MRTX1719，一种甲基硫腺苷协同 PRMT5 抑制剂，在 MTAP 缺失的肿瘤中表现出肿瘤特异性的 PRMT5 抑制作用，同时具有有限的免疫抑制作用。从机制上讲，转录组和蛋白质组谱分析表明，MRTX1719 成功地降低了 PI3K 通路的激活，PI3K 通路是一种有充分文献记载的免疫抵抗途径。它突出了 MRTX1719 克服 MTAP 缺失肿瘤免疫抵抗的潜力。此外，MRTX1719 使 MTAP 缺失肿瘤细胞对肿瘤反应性 T 细胞的杀伤更加敏感。在携带 MTAP 缺失肿瘤的小鼠中，MRTX1719 与抗 PD-1 联合使用可导致抗肿瘤活性的提高。
结论
总的来说，我们的结果为基于 MRTX1719 的 IO 组合在 MTAP 缺失肿瘤中的临床开发提供了强有力的理论依据和机制见解。
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