Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Flagship Labs 91, Inc., Cambridge, MA, USA.
Nat Cell Biol. 2022 Jul;24(7):1165-1176. doi: 10.1038/s41556-022-00942-8. Epub 2022 Jun 30.
CD8 T cells are central mediators of immune responses against infections and cancer. Here we identified Dapl1 as a crucial regulator of CD8 T cell responses to cancer and infections. Dapl1 deficiency promotes the expansion of tumour-infiltrating effector memory-like CD8 T cells and prevents their functional exhaustion, coupled with increased antitumour immunity and improved efficacy of adoptive T cell therapy. Dapl1 controls activation of NFATc2, a transcription factor required for the effector function of CD8 T cells. Although NFATc2 mediates induction of the immune checkpoint receptor Tim3, competent NFATc2 activation prevents functional exhaustion of CD8 T cells. Interestingly, exhausted CD8 T cells display attenuated NFATc2 activation due to Tim3-mediated feedback inhibition; Dapl1 deletion rescues NFATc2 activation and thereby prevents dysfunction of exhausted CD8 T cells in chronic infection and cancer. These findings establish Dapl1 as a crucial regulator of CD8 T cell immunity and a potential target for cancer immunotherapy.
CD8 T 细胞是针对感染和癌症的免疫反应的主要介质。在这里，我们确定 Dapl1 是癌症和感染的 CD8 T 细胞反应的关键调节剂。Dapl1 缺乏会促进肿瘤浸润效应记忆样 CD8 T 细胞的扩增，并防止其功能衰竭，同时增强抗肿瘤免疫和提高过继性 T 细胞治疗的效果。Dapl1 控制 NFATc2 的激活，NFATc2 是 CD8 T 细胞效应功能所必需的转录因子。虽然 NFATc2 介导免疫检查点受体 Tim3 的诱导，但 NFATc2 的有效激活可防止 CD8 T 细胞的功能衰竭。有趣的是，由于 Tim3 介导的反馈抑制，耗竭的 CD8 T 细胞显示出减弱的 NFATc2 激活；Dapl1 缺失可恢复 NFATc2 的激活，从而防止慢性感染和癌症中耗竭的 CD8 T 细胞功能障碍。这些发现确立了 Dapl1 作为 CD8 T 细胞免疫的关键调节剂和癌症免疫治疗的潜在靶点。
