Checkpoint blockade immunotherapies have demonstrated remarkable therapeutic success by overcoming tumor-induced T cell inhibition, however their efficacy is poor when patients lack evidence of a spontaneous T cell response. Overcoming key deficiencies in the tumor microenvironment that result in a lack of immune infiltration may be critically important for generating an anti-tumor T cell response and improving response rates to immunotherapy. Previous work from our laboratory has shown that tumors in mice which generate a spontaneous T cell response activate the innate immune system through the STING pathway. In all transplantable tumor models tested, STING agonists promote dendritic cell (DC) activation and the subsequent priming and recruitment of T cells, leading to significant tumor control. These findings have led to the rapid clinical development of therapeutic STING agonists. However, preliminary clinical trial results suggest that STING agonists have clinical activity in in only a minority of patients, and have limited efficacy in non-inflamed tumors, which represent the largest unmet clinical need. This suggests a need to more closely study the non- inflamed tumor microenvironment, and understand which innate immune cells and signaling pathways are required for driving tumor-specific T cell priming and recruitment in this context. We hypothesize that these questions may be addressed using the BRAF-activated, PTEN-deleted, ?-catenin- stabilized (BPC) genetic mouse model. Our laboratory has previously shown that tumors induced in these mice lack a spontaneous CD103+ DC and T cell infiltration and have low expression of the chemokines known to recruit these cells, namely CCL4 and CXCL9/10. We hypothesize that if we can recruit and activate CD103+ dendritic cells in these tumors, we will induce a tumor-specific T cell response and promote tumor control either alone or in combination with checkpoint blockade immunotherapy in this non-inflamed model. Our preliminary data suggest that STING agonists may be unsuccessful in generating productive T cell responses in non-inflamed tumors because BPC tumors also lack the required CD103+ DC subset for T cell priming and recruitment. To overcome the CD103+ dendritic cell defect in these tumors we propose to: 1) promote a chemokine gradient and vasculature permissible for CD103+ DC recruitment, 2) activate recruited DCs with a STING agonist, and 3) evaluate and enhance subsequent CD8+ T cell responses to promote tumor control. Ultimately our work has the potential to inform the treatment of patients with non-inflamed tumors and expand the subset of patients for whom immunotherapy is successful.
The proposed research will further our understanding of the mechanisms by which non-inflamed tumors limit immune cell entry and how those barriers may be overcome to induce an anti-tumor immune response. This research is directly relevant to public health because our findings identify new strategies for the treatment of cancer that might provide powerful combinations with current immunotherapies. Therefore, this work will directly support the NIH mission to seek fundamental knowledge about the nature of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness.
