[HTML][HTML] The host STING pathway at the interface of cancer and immunity

L Corrales, SM McWhirter… - The Journal of …, 2016 - Am Soc Clin Investig
L Corrales, SM McWhirter, TW Dubensky, TF Gajewski
The Journal of clinical investigation, 2016Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation