[PDF][PDF] Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12

CS Garris, SP Arlauckas, RH Kohler, MP Trefny… - Immunity, 2018 - cell.com
CS Garris, SP Arlauckas, RH Kohler, MP Trefny, S Garren, C Piot, C Engblom, C Pfirschke…
Immunity, 2018cell.com
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 …
Summary
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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