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Vornholz, L.* ; Isay, S.E.* ; Kurgyis, Z.* ; Strobl, D.C. ; Loll, P.* ; Mosa, M.H.* ; Luecken, M. ; Sterr, M. ; Lickert, H. ; Winter, C.* ; Greten, F.R.* ; Farin, H.F.* ; Theis, F.J. ; Ruland, J.*

Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy.

Sci. Adv. 9:eadd8564 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically "hot" niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)-deficient CRC required tumor cell-intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell-intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously "cold" TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell-intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mismatch Repair Deficiency; Colorectal-cancer; Tumors; Expression; Activation; Responses; Blockade; Cxcl10; Sensor; Web
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Journal Science Advances
Quellenangaben Volume: 9, Issue: 11, Pages: , Article Number: eadd8564 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Institute of Diabetes and Regeneration Research (IDR)
Institute of Lung Health and Immunity (LHI)
Institute of Stem Cell Research (ISF)
POF-Topic(s) 30205 - Bioengineering and Digital Health
90000 - German Center for Diabetes Research
30201 - Metabolic Health
30202 - Environmental Health
30204 - Cell Programming and Repair
Research field(s) Enabling and Novel Technologies
Helmholtz Diabetes Center
Lung Research
Stem Cell and Neuroscience
PSP Element(s) G-503800-001
G-501900-231
G-502300-001
G-505000-001
G-500800-001
Grants Leukemia & Lymphoma Society
European Research Council (ERC) under the European Union
Elite Network of Bavaria
Hessen State Ministry for Higher Education, Research and the Arts
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
Deutsche Forschungsgemeinschaft
German Federal Ministry of Health
Ministry of Higher Education, Research
Arts of the State of Hessen (HMWK)
DOI 10.1126/sciadv.add8564
WOS ID 000969832000006
Scopus ID 85150312004
PubMed ID 36921054
Erfassungsdatum 2023-10-06
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