PROJECT SUMMARY Follicular lymphoma (FL) arises from B lymphocytes and accounts for ~25% of non-Hodgkin’s lymphoma cases. With no existing curative treatments and only ~2.6% of cases resolving, FL is presently considered an incurable disease. New therapeutic approaches to therapeutically treat FL are thus critically needed. Contributing to the lack of efficacious therapies is the fact that both primary and secondary FL cases can arise in skin. Dermal lesions appear to exhibit unique immune resistance mechanisms making them a challenging lymphoma presentation to treat. Studies on immunotherapeutic response by dermal FL lesions are limited however by existing FL models. It is well accepted that the immune microenvironments in which most FL tumors arise and disseminate to – lymphoid tissues – are vastly different from the skin. A major gap in the field’s ability to develop new immunotherapies effective against skin FL is the gap in appropriate tumor models to test immunotherapies in the context their skin presentation. This project seeks to overcome this hurdle by designing a cell matrix vehicle that induces reliable and consistent tumor formation, as well as programmable immune infiltration for enhanced consistency and relevance to human disease to test immunotherapeutic efficacy against skin FL. The parent grant will utilize nanoparticle and bioconjugation technologies that when used together deliver molecular drugs to within lymph nodes to improve their therapeutic bioactivity. The proposed work under this supplement seeks to enable the evaluation of how abscopal effects elicited by the lymph node-targeted nanoformulation on lymphoma lesions that form in skin are altered by the local immune microenvironment of the skin tumor by engineering a matrix vehicle scaffold that enables consistent skin tumor formation. The goals of this proposal will be accomplished in a stepwise fashion. First, we will analyze effects of matrix vehicle composition on the formation rate, latency, and immune microenvironments of skin tumors formed from malignant lymphocytes from the Bcl6-EZH2 lymphoma model. Second, we will evaluate how lymph node- versus non-targeted chemoimmunotherapy control of skin lymphomas varies by the local immune microenvironment. Successful outcomes in this work will have broad significance and impact by establishing both a model system for immunotherapy testing relevant to human lymphoma as well as determining the effects of lymph node targeted therapies on eliciting robust abscopal effects against skin tumors.