TY - JOUR
T1 - STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors
AU - Woo, Seng Ryong
AU - Fuertes, Mercedes B.
AU - Corrales, Leticia
AU - Spranger, Stefani
AU - Furdyna, Michael J.
AU - Leung, Michael Y.K.
AU - Duggan, Ryan
AU - Wang, Ying
AU - Barber, Glen N.
AU - Fitzgerald, Katherine A.
AU - Alegre, Maria Luisa
AU - Gajewski, Thomas F.
N1 - Funding Information:
We thank J. Kline for critical reading of the manuscript; C. Nagler and H. Huang for providing Tlr4 −/− mice; R. Schreiber for the 1969 tumor cells; Y. Zheng for help with data analysis; and M. Gao for technical assistance. This work was supported by P01 CA97296 and R01 CA181160 from the National Cancer Institute and AI067497 to K.A.F.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/11/20
Y1 - 2014/11/20
N2 - Spontaneous Tcell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive Tcell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8+ Tcell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. Invitro, IFN-β production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment invivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-β production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.
AB - Spontaneous Tcell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive Tcell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8+ Tcell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. Invitro, IFN-β production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment invivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-β production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.
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U2 - 10.1016/j.immuni.2014.10.017
DO - 10.1016/j.immuni.2014.10.017
M3 - Article
C2 - 25517615
AN - SCOPUS:84912120595
VL - 41
SP - 830
EP - 842
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 5
ER -