STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade.

1. J Clin Invest. 2019 Jul 25;129(10):4350-4364. doi: 10.1172/JCI125413. STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade. Yang H(1)(2), Lee WS(1)(2), Kong SJ(1)(2), Kim CG(3), Kim JH(1)(2), Chang SK(4), Kim S(5), Kim G(5), Chon HJ(1)(2), Kim C(1)(2). Author information: (1)Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea. (2)Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, South Korea. (3)Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea. (4)Department of Radiation Oncology and. (5)Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea. The stimulator of interferon genes (STING) signaling pathway is a critical link between innate and adaptive immunity, and induces anti-tumor immune responses. STING is expressed in vasculatures, but its role in tumor angiogenesis has not been elucidated. Here we investigated STING-induced tumor vascular remodeling and the potential of STING-based combination immunotherapy. Endothelial STING expression was correlated with enhanced T-cell infiltration and prolonged survival in human colon and breast cancer. Intratumoral STING activation with STING agonists (cGAMP or RR-CDA) normalized tumor vasculatures in implanted and spontaneous cancers, but not in STING-deficient mice. These were mediated by upregulation of type I/II interferon genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in non-hematopoietic cells is as important as STING in hematopoietic cells to induce a maximal therapeutic efficacy of exogenous STING agonist. Vascular normalizing effects of STING agonists were dependent on type I interferon signaling and CD8+ T cells. Notably, STING-based immunotherapy was maximally effective when combined with VEGFR2 blockade and/or immune checkpoint blockade (αPD-1 or αCTLA-4), leading to complete regression of immunotherapy-resistant tumors. Our data show that intratumoral STING activation can normalize tumor vasculature and the tumor microenvironment, providing a rationale for combining STING-based immunotherapy and anti-angiogenic therapy. DOI: 10.1172/JCI125413 PMCID: PMC6763266 PMID: 31343989 [Indexed for MEDLINE] Conflict of interest statement: Conflict of interest: The authors have declared that no conflict of interest exists.