title: STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.
abstract: Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.
authors.affiliation: Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Olivier
authors.initials: O
authors.lastname: Demaria
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Aude
authors.initials: A
authors.lastname: De Gassart
authors.affiliation: Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Sanja
authors.initials: S
authors.lastname: Coso
authors.affiliation: Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gestermann
authors.affiliation: Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Di Domizio
authors.affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland;
authors.forename: Lukas
authors.initials: L
authors.lastname: Flatz
authors.affiliation: Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Olivier
authors.initials: O
authors.lastname: Gaide
authors.affiliation: Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland; Swiss Institute for Cancer Research, École polytechnique fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland;
authors.forename: Fabio
authors.initials: F
authors.lastname: Martinon
authors.affiliation: Division of Dermatology, and Departments of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland; michel.gilliet@chuv.ch.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D007109:Immunity; D015552:Injections, Intralesional; D007370:Interferon Type I / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D009712:Nucleotides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099197:STING Protein
chemical_list: D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; D007370:Interferon Type I; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D053633:Receptor, Interferon alpha-beta; C530855:Sting1 protein, mouse; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: CD8 T cells; STING; antitumor immunity; tumor endothelial cells; type I IFNs