LAUSR

Purpose: 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. Experimental Design: We examined the endothelial STING expression pattern and clinical implications in human malignancies. STING-induced vascular remodeling was studied using STING-deficient or wild-type mice. Implanted LLC tumors and transgenic MMTV-PyMT breast tumors were intratumorally injected with STING agonists (cGAMP or RR-CDA), with or without anti-VEGFR2 antibody and/or immune checkpoint inhibitors. The tumor microenvironment was evaluated by histologic and immune profiling analyses. Results: Endothelial STING expression was correlated with enhanced T-cell infiltration, reduced lymphovascular invasion, and prolonged survival in human colon and breast cancer. Intratumoral STING activation normalized tumor vasculatures, as shown by increased pericyte coverage and intact basement membrane, which was mediated by upregulation of vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a) and endothelial-lymphocyte interaction genes. These effects were dependent on type I interferon signaling and CD8+ T cells. STING activation also induced M1-like macrophage polarization within tumors. 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. Conclusions: 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. Citation Format: Hannah Yang, Hyojoong Kim, Joo Hoon Kim, Hong Jae Chon, Chan Kim. Intratumoral STING activation normalizes tumor vasculatures and synergizes with anti-angiogenic therapy to enhance cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3203.