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Review
. 2016 Jul 1;126(7):2404-11.
doi: 10.1172/JCI86892. Epub 2016 Jul 1.

The host STING pathway at the interface of cancer and immunity

Leticia Corrales, Sarah M McWhirter, Thomas W Dubensky Jr, Thomas F Gajewski
Review

The host STING pathway at the interface of cancer and immunity

Leticia Corrales et al. J Clin Invest. .

Abstract

A major subset of human cancers shows evidence for spontaneous adaptive immunity, which is reflected by the presence of infiltrating CD8+ T cells specific for tumor antigens within the tumor microenvironment. This observation has raised the question of which innate immune sensing pathway might detect the presence of cancer and lead to a natural adaptive antitumor immune response in the absence of exogenous infectious pathogens. Evidence for a critical functional role for type I IFNs led to interrogation of candidate innate immune sensing pathways that might be triggered by tumor presence and induce type I IFN production. Such analyses have revealed a major role for the stimulator of IFN genes pathway (STING pathway), which senses cytosolic tumor-derived DNA within the cytosol of tumor-infiltrating DCs. Activation of this pathway is correlated with IFN-β production and induction of antitumor T cells. Based on the biology of this natural immune response, pharmacologic agonists of the STING pathway are being developed to augment and optimize STING activation as a cancer therapy. Intratumoral administration of STING agonists results in remarkable therapeutic activity in mouse models, and STING agonists are being carried forward into phase I clinical testing.

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Figures

Figure 1
Figure 1. Scheme showing the activation of the STING pathway by cytosolic DNA.
Cytosolic DNA is recognized by cGAS, which catalyzes the generation of cGAMP. cGAMP binds to STING and leads to its activation, which involves translocation from the ER to perinuclear sites. This translocation results in the recruitment and activation of TBK1 by autophosphorylation. Active TBK1, in turn, phosphorylates the transcription factor IRF3, which translocates to the nucleus to induce transcription of type I IFN genes.
Figure 2
Figure 2. The STING pathway is activated within intratumoral DCs and boosts an adaptive immune response against tumors.
(A) Activation of STING in DCs by endogenous sources, most probably DNA released by dying tumor cells. DC activation via STING primes a low-level, endogenous T cell response that is insufficient to overcome the immunosupressive tumor microenvironment. Thus, tumor growth continues in spite of activation of STING in DCs. (B) Intratumoral injection of synthetic STING agonists directly stimulates the STING pathway. Synchronized activation of DCs in the tumor leads to markedly augmented priming of tumor-specific T cells in tumor-draining lymph nodes (LNs). Downstream, recruitment of effector T cells into the tumor microenvironment is facilitated by the release of the chemokines CXCL9/10 from DCs and other cells at the tumor site. Successfully recruited antigen-specific effector T cells promote tumor cell killing, leading to measurable tumor shrinkage (8).
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