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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.
Immunity (Cambridge, Mass.), 12/2018, Volume: 49, Issue: 6Journal Article
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. Display omitted •Effective anti-PD-1 anti-tumor responses require IL-12-producing dendritic cells•Anti-PD-1 indirectly activates IL-12 through IFN-γ produced from CD8+ T cells•Agonizing the non-canonical NF-κB pathway enhances dendritic cell IL-12 production•Combining aPD-1 with non-canonical NF-κB agonism enhances checkpoint immunotherapy Anti-PD-1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-γ released from drug-activated T cells. Furthermore, agonizing the non-canonical NF-κB pathway activates DCs and enhances aPD-1 therapy in an IL-12-dependent manner.
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