한빛사 논문
Hannah Yang1,4, Won Suk Lee1,4, So Jung Kong1,4, Chang Gon Kim5, Joo Hoon Kim1,4, Sei Kyung Chang2, Sewha Kim3, Gwangil Kim3, Hong Jae Chon1,4,* and Chan Kim1,4,*
1 Medical Oncology, 2 Department of Radiation Oncology, 3 Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 13495, Republic of Korea 4 Laboratory of Translational Immuno-Oncology, CHA University, Seongnam 13488, Republic of Korea 5 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea These authors contributed equally: Chan Kim, Hong Jae Chon
* Correspondence and requests for materials should be addressed to
Chan Kim, M.D., Ph.D. (Lead contact) Medical Oncology, CHA Bundang Medical Center, CHA University Medical School, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Korea
Hong Jae Chon, M.D., Ph.D. Medical Oncology, CHA Bundang Medical Center, CHA University Medical School, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Korea
Abstract
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.
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