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- W4297250188 abstract "Checkpoint blockade immunotherapy releases the inhibition of tumor-infiltrating lymphocytes (TILs) but weakly induces TIL proliferation. Exogenous IL-15 could further expand TILs and thus synergize with αPD-L1 therapy. However, systemic delivery of IL-15 extensively expands peripheral NK cells, causing severe toxicity. To redirect IL-15 to intratumoral PD-1+CD8+T effector cells instead of NK cells for better tumor control and lower toxicity, we engineered an anti–PD-1 fusion with IL-15-IL-15Rα, whose activity was geographically concealed by immunoglobulin Fc region with an engineered linker (αPD-1-IL-15-R) to bypass systemic NK cells. Systematic administration of αPD-1-IL-15-R elicited extraordinary antitumor efficacy with undetectable toxicity. Mechanistically, cis-delivery of αPD-1-IL-15-R vastly expands tumor-specific CD8+T cells for tumor rejection. Additionally, αPD-1-IL-15-R upregulated PD-1 and IL-15Rβ on T cells to create a feedforward activation loop, thus rejuvenating TILs, not only resulting in tumor control in situ, but also suppressing tumor metastasis. Collectively, renavigating IL-15 to tumor-specific PD-1+CD8+T cells, αPD-1-IL-15-R elicits effective systemic antitumor immunity." @default.
- W4297250188 created "2022-09-28" @default.
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- W4297250188 date "2022-09-27" @default.
- W4297250188 modified "2023-10-17" @default.
- W4297250188 title "An engineered concealed IL-15-R elicits tumor-specific CD8+T cell responses through PD-1-cis delivery" @default.
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- W4297250188 doi "https://doi.org/10.1084/jem.20220745" @default.
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