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
Date
02/07/2021Pubmed ID
33548597Pubmed Central ID
PMC8081932DOI
10.1016/j.jcmgh.2021.01.018Scopus ID
2-s2.0-85104314508 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
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.
Author List
Vonderhaar EP, Barnekow NS, McAllister D, McOlash L, Eid MA, Riese MJ, Tarakanova VL, Johnson BD, Dwinell MBAuthors
Michael B. Dwinell PhD Center Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinBryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Emily Vonderhaar in the CTSI department at Medical College of Wisconsin - CTSI
MESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptor, Interferon alpha-beta
Receptors, CXCR3
Signal Transduction
