Innate immune signaling and regulation in cancer immunotherapy

Abstract

A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

Figure 1

A central role of Batf3 DCs and the STING pathway in orchestrating anti-tumor T cell responses. Tumor cells displaying a T cell-inflamed phenotype produce chemokines, such as CCL4, which recruit Batf3 DCs. Tumor cell turnover and perhaps death results in the liberation of DNA and other DAMPs that gain access to infiltrating APCs, including DCs. Cytosolic DNA in APCs activates the STING pathway, resulting in the secretion of type I IFNs and also of the chemokines CXCL9 and CXCL10. Tumor endothelial cells can also contribute to the production of type I IFNs. This cytokine subsequently facilitates the activation of tumor-infiltrating Batf3 DCs, which take up tumor-associated antigens and migrate via the lymphatics to the tumor-draining lymph node, where they cross-prime tumor-specific CD8⁺ T cells. The activated CD8⁺ T cells undergo clonal expansion in the tumor-draining lymph node and traffic via the bloodstream. They are recruited back to the tumor microenvironment under the influence of CXCL9 and CXCL10 also released by Batf3 DCs in the tumor microenvironment. Dynamic movement of infiltrated CD8⁺ effector T cells results in direct contact with tumor cells, which can lead to tumor cell death. If tumor cells are not completely eliminated, then immune inhibitory pathways suppress T cell activation as part of a negative feedback loop.