Back to article: STING-driven activation of T cells: relevance for the adoptive cell therapy of cancer

FIGURE 1: STING agonist-induced effects on innate immune cells in the TME. Intratumoral injection of STING agonists induces repolarization of type-2 macrophages into type-1 macrophages, resulting in enhanced co-stimulation and differentiation of CD4+ and CD8+ T cells [39]. STING ligand-induced tumor cell death leads to the release of tumor-derived antigens and DNA, which are taken up by DCs, resulting in the release of type I IFNs and enhanced T cell activation [23][24][27]. Intratumoral injection of STING agonists results in the secretion of the chemokines CXCL9, CXCL10, and CXCL10, CXCL11, which are secreted by DCs and macrophages, respectively [37][41]. As a result, cytotoxic CD8+ T cells are recruited to the TME. STING agonists induces the secretion of type I IFN, leading to terminal differentiation of immature DCs and enhanced activation of DCs. Overall, intratumoral STING agonists injection leads to macrophage repolarization, DC cross-presentation, T cell trafficking, and DC maturation and activation, resulting in enhanced recruitment and activation of anti-tumor CD8+ T cells and improved tumor control.

23. Decout A, Katz JD, Venkatraman S, Ablasser A (2021). The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 21(9): 548-569. 10.1038/s41577-021-00524-z

24. Zhu Y, An X, Zhang X, Qiao Y, Zheng T, Li X (2019). STING: a master regulator in the cancer-immunity cycle. Mol Cancer 18(1): 152. 10.1186/s12943-019-1087-y

27. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA, Alegre ML, Gajewski TF (2014). STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41(5): 830-842. 10.1016/j.immuni.2014.10.017

37. de Mingo Pulido Á, Hänggi K, Celias DP, Gardner A, Li J, Batista-Bittencourt B, Mohamed E, Trillo-Tinoco J, Osunmakinde O, Peña R, Onimus A, Kaisho T, Kaufmann J, McEachern K, Soliman H, Luca VC, Rodriguez PC, Yu X, Ruffell B (2021). The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake. Immunity 54(6): 1154-1167.e1157. 10.1016/j.immuni.2021.04.019

39. Cheng N, Watkins-Schulz R, Junkins RD, David CN, Johnson BM, Montgomery SA, Peine KJ, Darr DB, Yuan H, McKinnon KP, Liu Q, Miao L, Huang L, Bachelder EM, Ainslie KM, Ting JP (2018). A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer. JCI Insight 3(22): e120638. 10.1172/jci.insight.120638

41. Ohkuri T, Kosaka A, Ishibashi K, Kumai T, Hirata Y, Ohara K, Nagato T, Oikawa K, Aoki N, Harabuchi Y, Celis E, Kobayashi H (2017). Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site. Cancer Immunol Immunother 66(6): 705-716. 10.1007/s00262-017-1975-1

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