Experimental development of strategies that effectively combine T cell immunotherapy with the inhibition of tumor-promoting signal transduction pathways for the treatment of melanoma

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The development of strategies that effectively combine T cell directed immunotherapy with the inhibition of tumor-promoting signal transduction pathways for the treatment of melanoma represents one of the most important current clinical challenges. The principle goal of this proposal is to experimentally evaluate such strategies using state-of-the-art preclinical genetically engineered mouse models. In our work we will investigate the general hypothesis that IFN-driven cytotoxic CD8+ T cell immunity is limited locally in the melanoma microenvironment by both physiologic protective responses and by the immunosuppressive activity of melanoma cells. These counter-regulatory mechanisms include the recruitment of myeloid immune cells into injured tumor tissue, the stimulation of PD1/PDL1 immune-inhibitory receptor interactions, and the generation of an immunosuppressive milieu by the activity of oncogenic signalling pathways in tumor cells. The experimental work is directed at interfering with these mechanisms and is divided in three parts with the following aims: (i) to characterize the role of type I IFNs for the regulation of anti-tumoral CD8+ T cell responses; (ii) to establish in vivo bioluminescence imaging techniques to non-invasively evaluate the efficacy of therapeutic strategies that modulate the infiltration of melanoma tissue with adoptively transferred cytotoxic CD8+ T cells and the subsequent recruitment of myeloid immune cells; and (iii) to expand our model system and explore treatment protocols that combine adoptive CD8+ T-cell therapies with BRAF(V600E) signal transduction inhibitors. The proposed experiments will yield fundamental insights into the possibilities to combine T cell immunotherapies with the inhibitors of tumor-promoting signal transduction pathways. This will provide valuable information for ongoing and future clinical translational studies in patients with metastatic melanoma.