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Cited by 61interferon and immune responsesPancreatic and Hepatic Oncology ResearchCancer Immunotherapy and Biomarkers

STING Activated Tumor-Intrinsic Type I Interferon Signaling Promotes CXCR3 Dependent Antitumor Immunity in Pancreatic Cancer

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Vonderhaar, Emily P., Barnekow, Nicholas S., McAllister, Donna, McOlash, Laura, Eid, Mahmoud Abu, Riese, Matthew J., Tarakanova, Vera L., Johnson, Bryon D. +1 more·2021·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2021.01.018PMC PMC8081932
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Abstract

Background & Aims Pancreatic ductal adenocarcinoma (PDA) is a lethal chemoresistant cancer that exhibits early metastatic spread. The highly immunosuppressive PDA tumor microenvironment renders patients resistant to emerging immune-targeted therapies. Building from our prior work, we evaluated stimulator of interferon genes (STING) agonist activation of PDA cell interferon-α/β-receptor (IFNAR) signaling in systemic antitumor immune responses. Methods PDA cells were implanted subcutaneously to wild-type, IFNAR-, or CXCR3-knockout mice. Tumor growth was monitored, and immune responses were comprehensively profiled. Results Human and mouse STING agonist ADU-S100 reduced local and distal tumor burden and activated systemic antitumor immune responses in PDA-bearing mice. Effector T-cell infiltration and inflammatory cytokine and chemokine production, including IFN-dependent CXCR3-agonist chemokines, were elevated, whereas suppressive immune populations were decreased in treated tumors. Intratumoral STING agonist treatment also generated inflammation in distal noninjected tumors and peripheral immune tissues. STING agonist treatment of type I IFN–responsive PDA tumors engrafted to IFNAR -/- recipient mice was sufficient to contract tumors and stimulate local and systemic T-cell activation. Tumor regression and CD8 + T-cell infiltration were abolished in PDA engrafted to CXCR3 -/- mice treated with STING agonist. Conclusions These data indicate that STING agonists promote T-cell infiltration and counteract immune suppression in locally treated and distant tumors. Tumor-intrinsic type I IFN signaling initiated systemic STING-mediated antitumor inflammation and required CXCR3 expression. STING-mediated induction of systemic immune responses provides an approach to harness the immune system to treat primary and disseminated pancreatic cancers.

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  • CD8+IFN-γ+ T cells are an effector population shown to be a target of downstream STING signaling involving the IFN-β-CXCL9/10 axis.

    “an effector population shown to be a target of downstream STING signaling involving the IFN-β-CXCL9/10 axis.54–58”

    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 [56]

    The Results section reports that STING agonist increased IFN-β expression and the frequency of CXCR3+CD8+ T cells in pancreatic tumor models. The Discussion links STING activation, type I interferon signaling, and CXCL9/CXCL10 to effector T-cell infiltration. Our copy does not establish that the affected CD8+ cells were specifically IFN-γ+. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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References 64 · Cited by 61

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Authors
Vonderhaar, E. P., Barnekow, N. S., McAllister, D., McOlash, L., Eid, M. A., Riese, M. J., Tarakanova, V. L., Johnson, B. D., & Dwinell, M. B.
Affiliations
Medical College of Wisconsin (US)
Corresponding author
Dwinell, Michael B.
ORCID
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2021
Volume
12
Issue
1
Pages
41-58
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2021.01.018
PMC
PMC8081932
OpenAlex
W3127873789
Cited by
61
References
64
Citations by year
2026: 8 · 2025: 7 · 2024: 15 · 2023: 12 · 2022: 14 · 2021: 5
FWCI
4.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01 CA226279, U01 CA178960)
  • National Institute of General Medical Sciences (T32 GM080202)
  • National Center for Advancing Translational Sciences (TL1 TR001437)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
STING agonist, pancreatic ductal adenocarcinoma, type I interferon signaling, IFNAR, CXCR3, antitumor immunity, CD8+ T cell infiltration, immunosuppressive tumor microenvironment, ADU-S100, systemic antitumor immune response, chemokines, chemoresistance
MeSH terms
STING Protein, Animals, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Cell Line, Tumor, Mice, Receptor, Interferon alpha-beta, Receptors, CXCR3

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