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

By Christopher S. Garris, S. Arlauckas, R. Kohler, Marcel P. Trefny, Seth B. Garren, Cécile Piot, Camilla Engblom, C. Pfirschke, Marie Siwicki, Jeremy Gungabeesoon and 13 more. Immunity, 2018

803 citations recorded by the source corpus.

&NA; 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 &ggr; (IFN‐&ggr;) 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‐&ggr; and IL‐12. Furthermore, we found that activating the non‐canonical NF‐&kgr;B 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. Graphical Abstract Figure. No caption available. HighlightsEffective anti‐PD‐1 anti‐tumor responses require IL‐12‐producing dendritic cellsAnti‐PD‐1 indirectly activates IL‐12 through IFN‐&ggr; produced from CD8+ T cellsAgonizing the non‐canonical NF‐&kgr;B pathway enhances dendritic cell IL‐12 productionCombining aPD‐1 with non‐canonical NF‐&kgr;B agonism enhances checkpoint immunotherapy &NA; 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‐&ggr; released from drug‐activated T cells. Furthermore, agonizing the non‐canonical NF‐&kgr;B pathway activates DCs and enhances aPD‐1 therapy in an IL‐12‐dependent manner.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/1209b0cd82a4fa3c176fbcbc8f01817d21cdace6

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Citations in the corpus

Single cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species (2019, methodology): “, 2016) but some of these cells can remain within tumors (Garris et al. 2018).”
Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, background): “A recent study by Garris, Pettit, and colleagues using intravital imaging provided evidence thatDCs could present tumor antigen to T cells within the tumor itself (32).”
NF-κB in biology and targeted therapy: new insights and translational implications (2024, background): “533 The upregulation of alternative NF-κ B pathway in tumor-in ﬁ ltrating DCs can be induced by anti-PD-1 treatment, leading to subsequent secretion of IL-12, which enhanced CD8 + T cell antitumor activity.”