mTOR regulates T cell exhaustion and PD-1 targeted immunotherapy response during chronic viral infection

• Type of Material: Article
• Authors: Satomi Ando, Cincinnati Children’s Hospital Medical Center; Charles M Perkins, Cincinnati Children’s Hospital Medical Center; Yamato Sajiki, Cincinnati Children’s Hospital Medical Center; Chase Chastain, Cincinnati Children’s Hospital Medical Center; Rajesh M Valanparambil, Emory University; Andreas Wieland, Emory University; William Hudson, Emory University; Masao Hashimoto, Emory University; Suresh Ramalingam, Emory University; Gordon J Freeman, Harvard Medical School; Rafi Ahmed, Emory University; Koichi Araki, Cincinnati Children’s Hospital Medical Center
• Language: English
• Date: 2022-11-15
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Ando et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI160025
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 132
• Issue: 22
• Keywords: Science & Technology; MEMORY; Research & Experimental Medicine; MAMMALIAN PROTEIN; PHOSPHORYLATION; SUSTAIN; Medicine, Research & Experimental; PROVIDE; FKBP12; SELECTION; DIFFERENTIATION; Life Sciences & Biomedicine; EXPRESSION; SUBSETS
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

Abstract

T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1–targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3+ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.