Interrogating mechanisms of a novel anti-tumor CD4 response 2308216

Abstract Introduction Agonists of the STING pathway, such as cyclic di-nucleotides (CDNs), exhibit powerful antitumor activity in preclinical models. CDN-driven tumor control has been primarily attributed to the activity of CD8 T cells, which recognize tumor-antigens presented on MHC I. We have found that CDN treatment also elicits strong responses against CD8-resistant MHC I-deficient tumors, including RMA-B2m-/- lymphoma cells, where both NK cells and CD4 T cells play crucial and at least partly independent roles in tumor control. NK cell-mediated clearance of B2m-/- tumors is expected, but little is known about how CD4 T cells mediate tumor clearance, particularly of MHC I-deficient tumors where CD4 T cell help of CD8 T cells is demonstrably irrelevant. Methods To identify the mechanisms by which CD4 T cells mediate tumor control, we conducted in vivo tumor growth experiments probing various mechanisms and phenotyped tumor-infiltrating immune cells under different conditions. Results The results rule out a role of direct MHC II recognition or death receptor signaling on tumor cells. Furthermore, they argue against a role for innate-like receptors on CD4 T cells. IFN-g produced by T cells after CDN treatment is crucial for tumor control but contrary to published paradigms, IFN-g receptor signaling in macrophages is dispensable for the anti-tumor response as are CD64+ macrophages. Notably, IFN-g receptor signaling in T cells contributes to tumor control, and is associated with a reduced frequency of tumoral regulatory T cells. However, the major impact of IFN-g in tumor control is on radioresistant cells. Alterations in the TME associated with IFN-g signaling on radioresistant cells will be discussed. Conclusion IFN-g produced by CD4 T cells plays a critical role in controlling MHC I-deficient tumors, independent of CD8 T cells, NK cells, CD64+ macrophages or expression of MHC II or death receptors on tumor cells. Its main impact on tumor control is on non-hematopoietic cells where it alters tumor progression. Funding Source R01CA270790 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)