Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity
Open accessAbstract
Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can partially bypass the requirement for STING-dependent activity from immune cells. Our findings reveal multiple, context-dependent roles for STING activity in the regulation of anti-tumor immunity and the response to immunotherapy. In preclinical models where STING is basally active, checkpoint inhibition is more likely to have a therapeutic effect and removal of STING signaling from either the tumor or the non-tumor compartment has a minimal effect. Removal of STING signaling in both, however, diminishes the efficacy derived from checkpoint therapy. Further work is needed to understand the heterogeneity of STING signaling in patients, both in tumor cells and the tumor microenvironment, and the best means of harnessing this pathway to generate anti-tumor immunity and improve therapeutic outcomes.
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Different tumor models have shown variability in their responses to STING signaling.
“As different tumor models have shown variability in their responses to STING signaling,66”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [66]
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References 29 · Cited by 22
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- [1]Tarbell KV Egen JG Breaking self-tolerance during autoimmunity and cancer immunity: myeloid cells and type I IFN response regulation J Leukoc Biol 2018 10.1002/JLB.3MIR1017-400R 29393979 · DOI
- [3]Diamond MS Kinder M Matsushita H Type I interferon is selectively required by dendritic cells for immune rejection of tumors J Exp Med 2011 208 1989 2003 10.1084/jem.20101158 21930769 PMC3182061 · DOI · Paper page
- [4]Woo SR Fuertes MB Corrales L STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors Immunity 2014 41 830 842 10.1016/j.immuni.2014.10.017 25517615 PMC4384884 · DOI · Paper page
- [5]Deng L Liang H Xu M STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors Immunity 2014 41 843 852 10.1016/j.immuni.2014.10.019 25517616 PMC5155593 · DOI · Paper page
- [7]Ho SS Zhang WY Tan NY The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells Immunity 2016 44 1177 1189 10.1016/j.immuni.2016.04.010 27178469 · DOI
- [9]Marcus A Mao AJ Lensink-Vasan M Wang L Vance RE Raulet DH Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response Immunity 2018 49 754 63.e4 10.1016/j.immuni.2018.09.016 30332631 PMC6488306 · DOI
- [10]Luteijn RD Zaver SA Gowen BG SLC19A1 transports immunoreactive cyclic dinucleotides Nature 2019 573 434 438 10.1038/s41586-019-1553-0 31511694 PMC6785039 · DOI · Paper page
- [11]Schadt L Sparano C Schweiger NA Cancer-cell-intrinsic cGAS expression mediates tumor immunogenicity Cell Rep 2019 29 1236 48.e7 10.1016/j.celrep.2019.09.065 31665636 · DOI
- [12]Klarquist J Hennies CM Lehn MA Reboulet RA Feau S Janssen EM STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells J Immunol 2014 193 6124 6134 10.4049/jimmunol.1401869 25385820 PMC4258444 · DOI
- [13]Homet Moreno B Zaretsky JM Garcia-Diaz A Response to programmed cell death-1 blockade in a murine melanoma syngeneic model requires costimulation, CD4, and CD8 T cells Cancer Immunol Res 2016 4 845 857 10.1158/2326-6066.CIR-16-0060 27589875 PMC5050168 · DOI
- [14]Kodumudi KN Siegel J Weber AM Scott E Sarnaik AA Pilon-Thomas S Immune checkpoint blockade to improve tumor infiltrating lymphocytes for adoptive cell therapy PLoS ONE 2016 11 e0153053 10.1371/journal.pone.0153053 27050669 PMC4822778 · DOI
- [15]Dufour JH Dziejman M Liu MT Leung JH Lane TE Luster AD IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking J Immunol 2002 168 3195 3204 10.4049/jimmunol.168.7.3195 11907072 · DOI · Paper page
- [16]Clark K Plater L Peggie M Cohen P Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation J Biol Chem 2009 284 14136 14146 10.1074/jbc.M109.000414 19307177 PMC2682862 · DOI
- [18]Canadas I Thummalapalli R Kim JW Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses Nat Med 2018 24 1143 1150 10.1038/s41591-018-0116-5 30038220 PMC6082722 · DOI
- [19]Stetson DB Ko JS Heidmann T Medzhitov R Trex1 prevents cell-intrinsic initiation of autoimmunity Cell 2008 134 587 598 10.1016/j.cell.2008.06.032 18724932 PMC2626626 · DOI · Paper page
- [22]Nakamura T Sato T Endo R Sasaki S Takahashi N Sato Y Hyodo M Hayakawa Y Harashima H STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation J Immunother Cancer 2021 10.1136/jitc-2021-002852 34215690 PMC8256839 · DOI
- [23]Ager CR Boda A Rajapakshe K High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege J Immunother Cancer 2021 10.1136/jitc-2021-003246 34341132 PMC8330562 · DOI
- [24]Song S Peng P Tang Z Decreased expression of STING predicts poor prognosis in patients with gastric cancer Sci Rep 2017 7 39858 10.1038/srep39858 28176788 PMC5296877 · DOI
- [25]Chen Q Boire A Jin X Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer Nature 2016 533 493 498 10.1038/nature18268 27225120 PMC5021195 · DOI · Paper page
- [28]Fu G Wu Y Zhao G Activation of cGAS-STING signal to inhibit the proliferation of bladder cancer: the immune effect of cisplatin Cells 2022 10.3390/cells11193011 36230972 PMC9564335 · DOI
- [29]Falahat R Berglund A Putney RM Perez-Villarroel P Aoyama S Pilon-Thomas S Barber GN Mule JJ Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma Proc Natl Acad Sci USA 2021 10.1073/pnas.2013598118 33827917 PMC8053941 · DOI · Paper page
- Authors
- Kim, J. C., Liu, X., Fitzgerald, K., Eng, J. S., Orf, J., O’Brien, S. A., Belmontes, B., Casbon, A.-J., Novitskiy, S. V., Tarbell, K. V., DeVoss, J., & Egen, J. G.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- DeVoss, Jason
- ORCID
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2022-11-17
- Volume
- 72
- Issue
- 5
- Pages
- 1327-1335
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- PMC
- PMC10110659
- OpenAlex
- W4309245102
- Cited by
- 22
- References
- 29
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 5
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cancer Immunology Immunotherapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- STING, cGAS-STING pathway, type I interferon, antitumor immunity, tumor microenvironment, B16F10 melanoma, MC38 colon carcinoma, immune checkpoint blockade, tumor immunogenicity, STING agonist, syngeneic mouse model
- MeSH terms
- STING Protein, DNA, Humans, Immunity, Innate, Immunotherapy, Interferon Type I, Neoplasms, Signal Transduction, Tumor Microenvironment
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