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 3

mTOR acts intrinsically in antigen-specific CD8+ T cells to regulate T cell exhaustion during chronic infection.

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mTOR acts intrinsically in antigen-specific CD8+ T cells to regulate T c...
LCMV-specific transgenic CD8+ T cells (P14 cells) were transduced with retrovirus expressing FKBP12 shRNA or scrambled shRNA. These retrovirus-transduced P14 cells (marked by Thy1.1) and nontransduced P14 cells were adoptively cotransferred into rapamycin-treated or untreated B6 mice followed by LCMV clone 13 infection. Rapamycin was i.p. administered every day from day –1 to day 9 after infection. See experimental design in Supplemental Figure 5. P14 cells were analyzed at day 10 after infection. (A) The flow cytometry plots, gated on retrovirus-transduced (Thy1.1+) or nontransduced (Thy1.1–) cells, show the frequency of stem-like (TIM3–TCF1+) and TIM3+ differentiated (TIM3+TCF1–) retrovirus-transduced and nontransduced P14 T cells in the spleen. (B) The frequency of stem-like (TIM3–TCF1+) and TIM3+ differentiated (TIM3+TCF1–) CD8+ T cells in retrovirus- transduced (green squares) and nontransduced (white circles) P14 cells in the spleen. n = 12 per each group for scrambled shRNA in the presence or absence of rapamycin. n = 8 per each group for FKBP12 shRNA in the presence or absence of rapamycin. Each line represents a comparison between nontransduced and transduced P14 cells in the same mice. Data were pooled from 4 independent experiments. P values were calculated by paired t test.