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Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15408-13. doi: 10.1073/pnas.1512832112. Epub 2015 Nov 25.

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

Author information

1
Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
2
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland;
3
Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland;
4
Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland;
5
Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
6
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;
7
Division of Dermatology, and Departments of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
8
Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland.
9
Department of Dermatology, University Hospital of Lausanne, 1011 Lausanne, Switzerland; michel.gilliet@chuv.ch.

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.

KEYWORDS:

CD8 T cells; STING; antitumor immunity; tumor endothelial cells; type I IFNs

PMID:
26607445
PMCID:
PMC4687570
DOI:
10.1073/pnas.1512832112
[Indexed for MEDLINE]
Free PMC Article

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