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Immunity. 2018 Dec 18;49(6):1148-1161.e7. doi: 10.1016/j.immuni.2018.09.024. Epub 2018 Dec 11.

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

Author information

1
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
2
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.
3
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.
4
Medical Oncology, Universitätsspital Basel, Basel, Switzerland; Cancer Immunology, Department of Biomedicine and Medical Oncology, University Hospital Basel, Switzerland.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
6
NanoString Technologies, 500 Fairview Ave N, Seattle, WA 98109, USA.
7
Oncosec Inc, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.
8
University of California, San Francisco Medical Center-Mt. Zion, 1600 Divisadero St, San Francisco, CA 94115, USA.
9
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
10
Medical Oncology, Universitätsspital Basel, Basel, Switzerland.
11
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA.
12
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA. Electronic address: mpittet@mgh.harvard.edu.

Abstract

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.

KEYWORDS:

IFN-γ; IL-12; anti-PD-1; cancer; checkpoint; dendritic cell; immunotherapy; non-canonical NF-κB

PMID:
30552023
PMCID:
PMC6301092
[Available on 2019-12-18]
DOI:
10.1016/j.immuni.2018.09.024

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