The impact of autophagy-driven intercellular communication in melanoma vasculature to restrain T cell-mediated anticancer immunity

Cutaneous malignant melanoma is one of the most aggressive cancer types. Recent antimelanoma immunotherapies have shown great promise but still face limited clinical success due to tumorinduced immunosuppression. Previous and preliminary data from the host lab demonstrated that the genetic disruption of autophagy (a major vesicular pathway, which is heightened in melanoma) in vascular endothelial cells reduces melanoma growth and metastasis and increases spontaneous tumor infiltration of CD8 positive Tcells. Interestingly, autophagy has recently been implicated in intercellular communication, which can occur via regulation of secreted and plasma membraneresiding proteins. However, whether and how this vesicular trafficking mechanism in the tumor vasculature impacts the immunosuppressive melanoma microenvironment has not been explored. Comforted by a set of promising preliminary results, I will test the hypothesis that autophagydriven intercellular communication in the stressed and abnormal tumor endothelium favors melanoma growth by inhibiting spontaneous and therapy-induced anticancer immunity. I will use a unique genetic model of autophagy deletion in the tumor endothelium, and a set of proteomics approaches, in vitro/ex vivo and in vivo assays to evaluate the impact of endothelial cell-associated autophagy in melanoma growth and dissemination. Finally I will assess the prognostic value of this autophagy-regulated mechanism in melanoma progression.