학술논문
Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12.
Document Type
Academic Journal
Author
Garris CS; 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.; Arlauckas SP; 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.; Kohler RH; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.; Trefny MP; Medical Oncology, Universitätsspital Basel, Basel, Switzerland; Cancer Immunology, Department of Biomedicine and Medical Oncology, University Hospital Basel, Switzerland.; Garren S; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.; Piot C; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.; Engblom C; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.; Pfirschke C; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.; Siwicki M; 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.; Gungabeesoon J; Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114, USA.; Freeman GJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.; Warren SE; NanoString Technologies, 500 Fairview Ave N, Seattle, WA 98109, USA.; Ong S; NanoString Technologies, 500 Fairview Ave N, Seattle, WA 98109, USA.; Browning E; Oncosec Inc, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.; Twitty CG; Oncosec Inc, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.; Pierce RH; Oncosec Inc, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.; Le MH; Oncosec Inc, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.; Algazi AP; University of California, San Francisco Medical Center-Mt. Zion, 1600 Divisadero St, San Francisco, CA 94115, USA.; Daud AI; University of California, San Francisco Medical Center-Mt. Zion, 1600 Divisadero St, San Francisco, CA 94115, USA.; Pai SI; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.; Zippelius A; Medical Oncology, Universitätsspital Basel, Basel, Switzerland.; Weissleder R; 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.; Pittet MJ; 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.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE
Subject
Language
English
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.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
(Copyright © 2018 Elsevier Inc. All rights reserved.)