Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Pediatric Hematology and Oncology, University of California, San Francisco Benioff Children's Hospital, San Francisco, CA 94158, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Rep. 2018 Jun 12;23(11):3262-3274. doi: 10.1016/j.celrep.2018.05.050.
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8 and CD4 effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
调节性 T 细胞（Tregs）对于维持免疫稳态至关重要，但它们在肿瘤组织中的存在会损害抗肿瘤免疫，并预示癌症患者预后不良。在这里，我们揭示了一种通过利用肿瘤中组蛋白 H3K27 甲基转移酶增强子结合蛋白 2（EZH2）的依赖性来选择性靶向和重新编程肿瘤浸润性 Tregs（TI-Tregs）的功能的机制。通过药理学或遗传学方法破坏 Tregs 中的 EZH2 活性，可促使 TI-Tregs 获得促炎功能，重塑肿瘤微环境，并增强招募和功能的 CD8 和 CD4 效应 T 细胞，从而消除肿瘤。此外，与普遍的 Treg 耗竭方法相比，EZH2 在 Tregs 中的功能丧失在机制上不同，效果更强，毒性更小。这项研究揭示了一种在癌症中靶向 Treg 的策略，通过在肿瘤中重新编程其功能来增强抗肿瘤免疫，从而减轻自身免疫。
