STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade
Hannah Yang, … , Hong Jae Chon, Chan Kim
Hannah Yang, … , Hong Jae Chon, Chan Kim
Published October 1, 2019; First published July 25, 2019
Citation Information: J Clin Invest. 2019;129(10):4350-4364. https://doi.org/10.1172/JCI125413.
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Categories: Research Article Angiogenesis Immunology

STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade

Abstract

The stimulator of IFN genes (STING) signaling pathway is a critical link between innate and adaptive immunity and induces antitumor 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 IFN genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in nonhematopoietic cells is as important as STING in hematopoietic cells for inducing a maximal therapeutic efficacy of exogenous STING agonists. Vascular normalizing effects of STING agonists were dependent on type I IFN 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 antiangiogenic therapy.

Authors

Hannah Yang, Won Suk Lee, So Jung Kong, Chang Gon Kim, Joo Hoon Kim, Sei Kyung Chang, Sewha Kim, Gwangil Kim, Hong Jae Chon, Chan Kim

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Figure 10

Triple combination immunotherapy efficiently delays tumor growth in both injected and noninjected tumors of a spontaneous breast cancer model.

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Triple combination immunotherapy efficiently delays tumor growth in both...
Tumor growth was measured twice a week in a spontaneous breast tumor model, MMTV-PyMT mice, starting from 9 weeks after birth. Mice were treated with STING agonist (S), DC101 (V), and/or αPD-1 (P). (A) Diagram depicting the treatment schedule. Red arrows indicate treatment, and black arrow indicates sacrifice. (B) Representative images showing gross appearances of tumors. Dotted lines demarcate palpable tumor nodules. Asterisks indicate PBS or STING-injected lesion. Red arrows indicate lesions with complete tumor regression. (C) Comparison of the growth of STING-injected or noninjected tumors in MMTV-PyMT mice. (D and E) Representative images (D) and comparisons (E) of CD8+ T cells, CD31+ blood vessels, and NG2+ pericyte coverage. n = 5 to 7 per group. Values are shown as mean ± SD. *P < 0.05, ANOVA with Tukey’s post hoc test (E). Scale bars: 50 μm.