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

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State: Public
Version: Final published version
Serval ID
serval:BIB_572BDFE9D6A6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Demaria O., De Gassart A., Coso S., Gestermann N., Di Domizio J., Flatz L., Gaide O., Michielin O., Hwu P., Petrova T.V., Martinon F., Modlin R.L., Speiser D.E., Gilliet M.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
2015
Volume
112
Number
50
Pages
15408-15413
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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
Animals, Antigens, Neoplasm/immunology, CD8-Positive T-Lymphocytes/immunology, CTLA-4 Antigen/immunology, Cell Proliferation/drug effects, Dendritic Cells/drug effects, Dendritic Cells/immunology, Disease Models, Animal, Dose-Response Relationship, Immunologic, Endothelial Cells/drug effects, Endothelial Cells/metabolism, Immunity, Injections, Intralesional, Interferon Type I/metabolism, Lymphocytes, Tumor-Infiltrating/drug effects, Lymphocytes, Tumor-Infiltrating/immunology, Melanoma/immunology, Melanoma/pathology, Melanoma, Experimental/immunology, Melanoma, Experimental/pathology, Membrane Proteins/metabolism, Mice, Inbred C57BL, Neoplasms/immunology, Neoplasms/pathology, Nucleotides, Cyclic/administration & dosage, Nucleotides, Cyclic/pharmacology, Receptor, Interferon alpha-beta/metabolism, Signal Transduction/drug effects
Pubmed
Web of science
Open Access
Yes
Create date
07/12/2015 11:07
Last modification date
20/08/2019 14:11
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