Contribution of the cutaneous APC network to melanoma progression and therapy.

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DESCRIPTION (provided by applicant): Melanoma is an extremely difficult disease to treat. Chemotherapy is notoriously ineffective with a negligible long-term remission rate. Recent studies have established that inhibition of BRAF signaling induces massive melanoma cell death leading to response rates exceeding 50% in patients who test positive for the BRAFV600E mutation. Responses unfortunately are transient, lasting on average 6.8 months and eventually all patients' progress or relapse. In contrast, immunotherapy can produce long-lasting cures in a small minority of patients. Combination of these approaches is therefore extremely attractive. BRAF inhibition induces cell death and the release of melanoma antigens in patients. This is exciting for the melanoma field because chemotherapy does not reliably kill melanoma tumors in patients. Recent studies suggest that dying tumor cells can be excellent sources of antigen for immunotherapy. BRAF inhibition therefore, because it causes massive tumor cell death, represents a unique opportunity to develop novel effective immunotherapies. This proposal aims to identify immune mediated strategies able to potentiate clinical remissions induced by BRAF inhibition. The study proposed herein provides the first comprehensive assessment of the contribution of cutaneous DC and macrophages to the development, or the lack thereof, of therapeutic immunity to BRAF inhibitors using an inducible model of BRAF-driven tumors. We find this to be of great importance as endogenous vaccination due to BRAF-inhibition-induced melanoma cell death could offer a novel approach to melanoma immunotherapy. Such an approach could overcome numerous drawbacks in the vaccination strategies currently in use. In the last ten years, our group of investigators has provided evidence that the expansion of endogenous DCs followed by their activation might be a valid strategy to promote antitumor immunity in several mouse tumor models. Here, we propose advancing a step further and testing whether combining BRAF inhibitors to increase tumor antigen availability, together with vaccination strategies aimed at expanding and activating tumor-associated CD103+ DC in situ while eliminating tumor-associated immunosuppressive APC via CSF-1R Ab (already in cancer Phase I trial), could prolong response to BRAF therapy. Combination therapy with BRAF inhibitors and immunotherapy is urgently needed by melanoma patients. Results of this study are expected to provide a rationale for the design of key clinical trials to treat this devastating disease.