The STING pathway and the T cell-inflamed tumor microenvironment

Abstract

A major subset of patients with advanced solid tumors show a spontaneous T cell-inflamed tumor microenvironment, which has prognostic import and is associated with clinical response to immunotherapies. As such, understanding the mechanisms governing the generation of spontaneous T cell responses in only a subset of patients is critical for advancing immunotherapeutic approaches further. Here, we discuss the characteristics of T cell-inflamed versus non-inflamed tumors, including a type I interferon (IFN) signature associated with T cell priming against tumor antigens. We review recent findings that have pointed towards the STING (stimulator of interferon genes) pathway of cytosolic DNA sensing as an important innate immune sensing mechanism driving type I IFN production in the tumor context. Knowledge of this pathway is guiding the further development of novel immunotherapeutic strategies.

Figure 1. Model for STING pathway activation by cytosolic DNA

The appearance of DNA in the cytosol engages cGAS, which generates intracellular cyclic dinucleotides as a second messenger. This results in aggregation of STING, which leads to TBK1 phosphorylation and activation, which in turn phosphorylates the transcription factor IRF3. The latter contributes directly to transcription of type I IFN genes.

Figure 2. Working model for innate immune sensing leading to spontaneous anti-tumor T cell responses in vivo

Tumor-derived DNA, presumably generated during tumor cell stress or death, can be found within the cytosol of intratumoral DCs. This is associated with STING pathway activation and IFN-β production. The use of gene-targeted mice has revealed a critical role for STING, IRF3, type I IFN production and sensing, and the Batf3-lineage of DCs for spontaneous anti-tumor T cell responses in vivo. STING pathway activation also leads to chemokine production, which likely contributes to effector T cell recruitment into the inflamed tumor microenvironment.