Humblin Etienne, Korpas Isabel, Prokhnevska Nataliya, Vaidya Abishek, Lu Jiahua, van der Heide Verena, Filipescu Dan, Bobrowski Tesia, Marks Adam, Park Matthew D, Bernstein Emily, Brown Brian D, Lujambio Amaia, Dominguez-Sola David, Rosenberg Brad R, Kamphorst Alice O
bioRxiv. 2024 Sep 20:2024.09.16.611518. doi: 10.1101/2024.09.16.611518.
During persistent antigen stimulation, PD-1 CD8 T cells are maintained by progenitor exhausted PD-1 TCF-1 CD8 T cells (Tpex). Tpex respond to PD-1 blockade, and regulation of Tpex differentiation into more functional Tex is of major interest for cancer immunotherapies. Tpex express high levels of Inducible Costimulator (ICOS), but the role of ICOS for PD-1 CD8 T cell responses has not been addressed. In chronic infection, ICOS-deficiency increased both number and quality of virus-specific CD8 T cells, with accumulation of effector-like Tex due to enhanced survival. Mechanistically, loss of ICOS signaling potentiated FoxO1 activity and memory-like features of Tpex. In mice with established chronic infection, ICOS-Ligand blockade resulted in expansion of effector-like Tex and reduction in viral load. In a mouse model of hepatocellular carcinoma, ICOS inhibition improved cytokine production by tumor-specific PD-1 CD8 T cells and delayed tumor growth. Overall, we show that ICOS limits CD8 T cell responses during chronic antigen exposure.
在持续的抗原刺激过程中，PD-1⁺ CD8 T细胞由祖细胞耗竭型PD-1⁺ TCF-1⁺ CD8 T细胞（Tpex）维持。Tpex对PD-1阻断有反应，并且将Tpex分化为更具功能的Tex的调控是癌症免疫疗法的主要研究兴趣点。Tpex表达高水平的诱导性共刺激分子（ICOS），但ICOS在PD-1⁺ CD8 T细胞反应中的作用尚未得到研究。在慢性感染中，ICOS缺陷增加了病毒特异性CD8 T细胞的数量和质量，由于存活率提高，效应样Tex细胞积累。从机制上讲，ICOS信号缺失增强了FoxO1活性以及Tpex的记忆样特征。在已建立慢性感染的小鼠中，ICOS配体阻断导致效应样Tex细胞扩增并降低病毒载量。在肝细胞癌小鼠模型中，ICOS抑制改善了肿瘤特异性PD-1⁺ CD8 T细胞的细胞因子产生并延缓了肿瘤生长。总体而言，我们表明ICOS在慢性抗原暴露期间限制CD8 T细胞反应。
