Proteotoxic stress response drives T cell exhaustion and immune evasion

• 成果类型: Article
• 署名作者: Wang, Yi; Ma, Anjun; Song, No-Joon; Shannon, Ariana E.; Amankwah, Yaa S.; Chen, Xingyu; Wu, Weidong; Wang, Ziyu; Saadey, Abbey A.; Yousif, Amir; Ghosh, Gautam; Mandula, Jay K.; Velegraki, Maria; Xiao, Tong; Wen, Haitao; Huang, Stanley Ching-Cheng; Wang, Ruoning; Beusch, Christian M.; Dawood, Abdelhameed S.; Gordon, David E.; Abdel-Hakeem, Mohamed S.; Ghoneim, Hazem E.; Xin, Gang; Searle, Brian C.; Li, Zihai
• 署名单位: James Cancer Hospital & Solove Research Institute; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; Johns Hopkins University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; Nationwide Childrens Hospital; Research Institute at Nationwide Children's Hospital; Center for Childhood Cancer & Blood Diseases; Emory University; Uppsala University; University System of Ohio; Ohio State University
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09539-1
• 发表日期: 2025-11-27
• 关键词: hematopoietic stem-cells; heat-shock; expression; gene; chaperone; LINKS; gp96; architecture; proteomics; infection

摘要

Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1, 2, 3-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.