Grinberg-Bleyer Yenkel, Oh Hyunju, Desrichard Alexis, Bhatt Dev M, Caron Rachel, Chan Timothy A, Schmid Roland M, Klein Ulf, Hayden Matthew S, Ghosh Sankar
Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cell. 2017 Sep 7;170(6):1096-1108.e13. doi: 10.1016/j.cell.2017.08.004.
Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.
调节性T细胞（Tregs）在抑制抗肿瘤免疫反应中起关键作用。因此，了解调控Treg细胞稳态的机制对于开发有效的肿瘤免疫疗法可能至关重要。我们最近证明了经典核因子κB（NF-κB）亚基p65和c-Rel在Treg细胞的特性和功能中起关键作用。在本报告中，我们表明NF-κB的c-Rel缺失特异性损害了活化Treg细胞（aTreg）亚群的产生和维持，已知该亚群在肿瘤部位富集。使用小鼠模型，我们证明在Tregs中缺乏c-Rel而非p65的小鼠中，黑色素瘤的生长显著降低。此外，对c-Rel功能的化学抑制通过损害aTreg介导的免疫抑制作用延迟了黑色素瘤的生长，并增强了抗PD-1免疫疗法的效果。因此，我们的研究确立了抑制NF-κB的c-Rel作为增强检查点靶向免疫治疗方案的可行治疗方法。
