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Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12.
- Garris, Christopher S;
- Arlauckas, Sean P;
- Kohler, Rainer H;
- Trefny, Marcel P;
- Garren, Seth;
- Piot, Cécile;
- Engblom, Camilla;
- Pfirschke, Christina;
- Siwicki, Marie;
- Gungabeesoon, Jeremy;
- Freeman, Gordon J;
- Warren, Sarah E;
- Ong, SuFey;
- Browning, Erica;
- Twitty, Christopher G;
- Pierce, Robert H;
- Le, Mai H;
- Algazi, Alain P;
- Daud, Adil I;
- Pai, Sara I;
- Zippelius, Alfred;
- Weissleder, Ralph;
- Pittet, Mikael J
Published Web Location
https://doi.org/10.1016/j.immuni.2018.09.024Abstract
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
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