期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 12, 期 1, 页码 41-58出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2021.01.018
关键词
Antitumor Immunity; Tumor Microenvironment; Flow Immunophenotyping; Tumor-Intrinsic IFNAR Signaling
资金
- NCI [U01 CA178960, R01 CA226279]
- Advancing a Healthier Wisconsin Endowment
- Bobbie Nick Voss Charitable Foundation
- NIGMS [T32 GM080202]
- Clinical & Translational Science Institute of Southeast Wisconsin
- NCATS [TL1 TR001437]
STING agonists can promote T-cell infiltration, counteract immune suppression, and generate systemic anti-tumor inflammation in locally treated and distant tumors.
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-alpha/beta-receptor (IFNAR) signaling in systemic antitumor immune responses. METHODS: PDA cells were implanted subcutaneously to wildtype, 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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