1. Academic Validation
  2. STING Activated Tumor-Intrinsic Type I Interferon Signaling Promotes CXCR3 Dependent Antitumor Immunity in Pancreatic Cancer

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

  • Cell Mol Gastroenterol Hepatol. 2021;12(1):41-58. doi: 10.1016/j.jcmgh.2021.01.018.
Emily P Vonderhaar 1 Nicholas S Barnekow 2 Donna McAllister 2 Laura McOlash 2 Mahmoud Abu Eid 2 Matthew J Riese 3 Vera L Tarakanova 2 Bryon D Johnson 1 Michael B Dwinell 4
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; LaBahn Pancreatic Cancer Program, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 2 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 3 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; LaBahn Pancreatic Cancer Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Versiti Blood Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 4 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin; LaBahn Pancreatic Cancer Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: mdwinell@mcw.edu.
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.

Keywords

Antitumor Immunity; Flow Immunophenotyping; Tumor Microenvironment; Tumor-Intrinsic IFNAR Signaling.

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