mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection
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 en...
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| Format: | Članak |
| Jezik: | English |
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American Society for Clinical Investigation
2023-01-01
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| Serija: | The Journal of Clinical Investigation |
| Teme: | |
| Online pristup: | https://doi.org/10.1172/JCI160025 |
| _version_ | 1827768215072145408 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Satomi Ando |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:12Z |
| format | Article |
| id | doaj.art-dfaca50a88f74b02a4c1d34e9ba0a73c |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:12Z |
| publishDate | 2023-01-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-dfaca50a88f74b02a4c1d34e9ba0a73c2023-11-07T16:19:47ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-01-011332mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infectionSatomi AndoCharles M. PerkinsYamato SajikiChase ChastainRajesh M. ValanparambilAndreas WielandWilliam H. HudsonMasao HashimotoSuresh S. RamalingamGordon J. FreemanRafi AhmedKoichi ArakiT 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.https://doi.org/10.1172/JCI160025ImmunologyInfectious disease |
| spellingShingle | 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 mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection The Journal of Clinical Investigation Immunology Infectious disease |
| title | mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection |
| title_full | mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection |
| title_fullStr | mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection |
| title_full_unstemmed | mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection |
| title_short | mTOR regulates T cell exhaustion and PD-1–targeted immunotherapy response during chronic viral infection |
| title_sort | mtor regulates t cell exhaustion and pd 1 targeted immunotherapy response during chronic viral infection |
| topic | Immunology Infectious disease |
| url | https://doi.org/10.1172/JCI160025 |
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