mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection
Satomi Ando, Charles M. Perkins, Yamato Sajiki, Chase Chastain, Rajesh M. Valanparambil, Andreas Wieland, William H. Hudson, Masao Hashimoto, Suresh S. Ramalingam, Gordon J. Freeman, Rafi Ahmed, Koichi Araki
Satomi Ando, Charles M. Perkins, Yamato Sajiki, Chase Chastain, Rajesh M. Valanparambil, Andreas Wieland, William H. Hudson, Masao Hashimoto, Suresh S. Ramalingam, Gordon J. Freeman, Rafi Ahmed, Koichi Araki
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Research Article Immunology Infectious disease

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

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.

Authors

Satomi Ando, Charles M. Perkins, Yamato Sajiki, Chase Chastain, Rajesh M. Valanparambil, Andreas Wieland, William H. Hudson, Masao Hashimoto, Suresh S. Ramalingam, Gordon J. Freeman, Rafi Ahmed, Koichi Araki

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Figure 5

mTOR inhibition impairs antiviral T cell immunity by decreasing the generation of effector-like transitory T cells from stem-like T cells after establishing chronic infection.

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mTOR inhibition impairs antiviral T cell immunity by decreasing the gene...
(A–G) Mice were infected with LCMV clone 13, and then rapamycin was administered daily i.p. to the mice from day 31 or 36 to day 62 or 67, respectively. Analyses were performed in spleens 1 month after rapamycin treatment. (A) Experimental design. (B) The frequency of DbGP33+ cells in the spleen (gated on CD8). (C) The total number of DbGP33+, DbGP276+, and PD-1+CD8+ T cells in the spleen. (D) The frequency of stem-like (TIM3–TCF1+) and TIM3+ differentiated (TIM3+TCF1–) cells in the spleen (gated on DbGP33+ CD8). (E) The number of TIM3+ differentiated (TIM3+TCF1–) or (G) stem-like (TIM3–TCF1+) CD8+ T cells in the spleen is shown for DbGP33+, DbGP276+, and PD-1+CD8+ T cells. (F) Viral titers in spleens. (C and E–G) n = 10 for control and n = 9 for rapamycin group. (H–J) Stem-like CD8+ T cells (TIM3–CXCR5+PD1+) were sorted from spleens of chronically infected mice (CD45.2+) at more than 30 days after infection. Sorted cells were transferred into chronically infected mice (>day 30 after infection, CD45.1+). BrdU-containing drinking water was given recipient mice. Rapamycin was administered daily for 10 days starting 1 day prior to adoptive transfer. (H) Experimental design. Tx, treatment. (I and J) The frequency of (I) BrdU+ cells and (J) effector-like transitory (CX3CR1+TIM3+) cells in PD1+CD45.2+CD8+ T cells in the spleen (flow plots, gated on PD1+CD45.2+ CD8). Each symbol represents an individual mouse. Each bar in C and E–G and each horizontal line in F represents geometric means. Each bar in I and J represents means. P values were calculated by unpaired t test. Data were pooled from 2 independent experiments.