STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade
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
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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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 7

TME regulation by STING activation is dependent on type I IFN signaling and CD8+ T cells.

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TME regulation by STING activation is dependent on type I IFN signaling ...
Mice were subcutaneously implanted with LLC tumor cells and treated with STING agonist (S) and depleting antibodies for IFNAR (αIFNAR) or CD8+ T cells (αCD8). (A and B) Comparison of tumor growth in mice. Mean (A) and individual (B) tumor growth curves over time. Red arrows indicate injections of cGAMP (10 μg), blue arrows indicate injections of depleting antibodies, and black arrow indicates sacrifice. (C and D) Representative images (C) and comparisons (D) of CD8+ T cells, CD31+ blood vessels, NG2+ pericyte coverage, and COL4+ BM coverage. §P < 0.05 versus S + αIFNAR. (E–G) Comparison of gene expression involved in vascular stabilization (E), vascular destabilization (F), and endothelial-lymphocyte interaction (G). Pooled data from 2 experiments with n = 6 per group. Values are shown as mean ± SD. *P < 0.05 versus PBS; #P < 0.05 versus S. ANOVA with Tukey’s post hoc test (A and D–G). Scale bars: 50 μm.