美国俄亥俄州立大学Hazem E. Ghoneim团队近期取得重要工作进展，他们研究发现耗竭T细胞中TGFβ1/BMP信号的重新平衡开启对免疫检查点阻断疗法的响应能力。相关研究成果2022年12月21日在线发表于《自然—免疫学》杂志上。

据介绍，T细胞功能障碍会阻碍慢性感染和癌症的清除。此外，功能失调的CD8⁺ T细胞的表观遗传编程限制了它们对免疫疗法的反应，包括免疫检查点阻断（ICB）。然而，目前尚不清楚哪些上游信号驱动了功能失调的表观遗传程序的获得，以及治疗靶向这些信号是否能将最终功能失调的T细胞重塑为ICB反应状态。

研究人员开发了一种稳定的人T细胞功能障碍体外模型系统，并表明后效应CD8⁺ T细胞中慢性TGFβ1信号通过稳定的表观遗传变化加速其终端功能障碍。相反，在阻断TGFβ1的同时，增强骨形态发生蛋白（BMP）信号，在慢性受刺激的人CD8⁺ T细胞中保留效应和记忆程序，诱导对肿瘤的应答反应，并在慢性病毒感染期间协同ICB反应。

因此，重新平衡TGFβ1/BMP信号为释放功能失调的CD8⁺ T细胞和增强T细胞免疫治疗提供了一种令人兴奋的新方法。

附：英文原文

Title: Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy

Author: Saadey, Abbey A., Yousif, Amir, Osborne, Nicole, Shahinfar, Roya, Chen, Yu-Lin, Laster, Brooke, Rajeev, Meera, Bauman, Parker, Webb, Amy, Ghoneim, Hazem E.

Issue&Volume: 2022-12-21

Abstract: T cell dysfunctionality prevents the clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB). However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here we innovate an in vitro model system of stable human T cell dysfunction and show that chronic TGFβ1 signaling in posteffector CD8+ T cells accelerates their terminal dysfunction through stable epigenetic changes. Conversely, boosting bone morphogenetic protein (BMP) signaling while blocking TGFβ1 preserved effector and memory programs in chronically stimulated human CD8+ T cells, inducing superior responses to tumors and synergizing the ICB responses during chronic viral infection. Thus, rebalancing TGFβ1/BMP signals provides an exciting new approach to unleash dysfunctional CD8+ T cells and enhance T cell immunotherapies.

DOI: 10.1038/s41590-022-01384-y

Source: https://www.nature.com/articles/s41590-022-01384-y