Basavaraja Raghavendra, Zhang Hongru, Holczbauer Ágnes, Lu Zhen, Radaelli Enrico, Assenmacher Charles-Antoine, George Subin S, Nallamala Vamshidhar C, Beiting Daniel P, Meyer-Ficca Mirella L, Meyer Ralph G, Guo Wei, Fan Yi, Modzelewski Andrew J, Spiegelman Vladimir S, Cohen Michael S, Fuchs Serge Y
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep Med. 2024 Jul 16;5(7):101649. doi: 10.1016/j.xcrm.2024.101649.
Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.
肿瘤浸润调节性T细胞（TI-Tregs）在肿瘤微环境（TME）中发挥免疫抑制作用，导致实体瘤加速生长并对免疫疗法产生抗性。在此，我们证明聚（ADP-核糖）聚合酶-11（PARP11）是TI-Tregs免疫抑制活性的关键调节因子。PARP11的表达与癌症患者体内TI-Treg细胞数量以及对免疫检查点阻断（ICB）的不良反应相关。包括腺苷和前列腺素E2在内的肿瘤衍生因子可诱导TI-Tregs中PARP11的表达。在TME细胞中敲除PARP11或用选择性PARP11抑制剂ITK7处理荷瘤小鼠，可使TI-Tregs失活并恢复抗肿瘤免疫反应。因此，ITK7可减缓肿瘤生长，并显著提高包括ICB和嵌合抗原受体（CAR）T细胞过继性转移在内的抗肿瘤免疫疗法的疗效。这些结果表明PARP11是TI-Treg活性的关键驱动因子以及免疫抑制性TME的主要调节因子，并支持将PARP11作为增强抗癌免疫疗法的靶点。
