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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.

Immunity (Cambridge, Mass.), 2018-12, Vol.49 (6), p.1148-1161.e7 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12
Autor: 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.
Assuntos: Adult ; Aged ; Aged, 80 and over ; Animal models ; Animals ; anti-PD-1 ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - immunology ; Anticancer properties ; Antitumor activity ; Cancer ; Cancer immunotherapy ; Cell activation ; checkpoint ; Crosstalk ; Cytokines ; Cytotoxicity ; dendritic cell ; Dendritic cells ; Dendritic Cells - immunology ; Dendritic Cells - metabolism ; Experiments ; Female ; Gene expression ; Gene sequencing ; Grants ; Humans ; IFN-γ ; IL-12 ; Immune checkpoint ; Immunity ; Immunotherapy ; Immunotherapy - methods ; Interferon ; Interferon-gamma - immunology ; Interferon-gamma - metabolism ; Interleukin 12 ; Interleukin-12 - administration & dosage ; Interleukin-12 - immunology ; Interleukin-12 - metabolism ; Lymphocytes ; Lymphocytes T ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy ; Middle Aged ; Neoplasms - immunology ; Neoplasms - metabolism ; Neoplasms - therapy ; NF-kappa B - immunology ; NF-kappa B - metabolism ; NF-κB protein ; non-canonical NF-κB ; PD-1 protein ; Pharmacodynamics ; Pharmacology ; Programmed Cell Death 1 Receptor - antagonists & inhibitors ; Programmed Cell Death 1 Receptor - immunology ; Programmed Cell Death 1 Receptor - metabolism ; Proteins ; Research funding ; Ribonucleic acid ; RNA ; Signal Transduction - drug effects ; Signal Transduction - immunology ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Tumors ; γ-Interferon
É parte de: Immunity (Cambridge, Mass.), 2018-12, Vol.49 (6), p.1148-1161.e7
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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C.S.G. and S.P.A. designed the study , performed experiments, analyzed data, and wrote the manuscript. R.H.K., M.P.T., S.G., C.Pi., C.E., C. Pf, M.S., J.G., S.E.W., S.O., E.B., R.H.P. and M.H.L. performed experiments and generated and analyzed data. G.J.F, C.G.T., A.P.A., A.I.D., A.Z. and R.W provided input for research design and interpretation and edited the manuscript. M.J.P. directed the study and wrote the manuscript.
Author Contributions
Descrição: 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12

United States: Elsevier Inc

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