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- W4385686733 abstract "Abstract Antigen-specific CD8 T cells gradually have impaired functions in chronic infection and cancers, which is termed T cell exhaustion. Since T cell exhaustion is associated with programmed death 1 (PD-1), the blockade of PD-1 pathway reinvigorates exhausted CD8 T cells, resulting in better control of infection and cancers. Stem-like CD8 T cells are important for maintenance of antigen-specific CD8 T cells during chronic infection and cancers because they have self-renewal ability and provide effector-like CD8 T cells which possess transiently cytotoxicity. PD-1 targeted therapies enhance functional T cells response by promoting differentiation of stem-like CD8 T cells toward effector-like CD8 T cells. mTOR is a serine/threonine kinase that regulates cellular functions and proliferation. However, the role of mTOR during T cell exhaustion and PD-1 targeted therapies remains elusive. Here, we found that mTOR inhibition enhanced accumulation of stem-like CD8 T cells at the early phase of infection, leading to improved efficacy of PD-1 blockade. In contrast, after the establishment of chronic LCMV infection, mTOR inhibition suppressed the transition to effector-like CD8 T cells from stem-like CD8 T cells. Mechanistically, a cell intrinsic mTOR signal was critical for differentiation of stem-like CD8 T cells into effector-like CD8 T cells during chronic infection as well as PD-1 targeted therapy. Thus, simultaneous treatments of PD-1 blockade with mTOR inhibition failed to induce effector-like CD8 T cells, resulting in reduced efficacy of PD-1 targeted therapy. Our data demonstrate that mTOR signals regulate T cell exhaustion and PD-1 targeted therapy and have important implications for combination cancer therapies with PD-1 blockade. Supported by grants from NIH (R01 AI139675)" @default.
- W4385686733 created "2023-08-10" @default.
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- W4385686733 date "2023-05-01" @default.
- W4385686733 modified "2023-09-29" @default.
- W4385686733 title "mTOR signals regulate T cell exhaustion and T cell responses during PD-1 targeted immunotherapy in chronic viral infection." @default.
- W4385686733 doi "https://doi.org/10.4049/jimmunol.210.supp.68.12" @default.
- W4385686733 hasPublicationYear "2023" @default.
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