Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma.

3011 Background: T cell-targeted checkpoint inhibitor immunotherapy for melanoma and other solid tumor malignancies only benefits a subpopulation of patients. Our work has shown that melanoma-expressed factors including TGF-β can generate an immune privileged site by suppressing the function of critical dendritic cell populations within the local immune microenvironment. We hypothesized that inhibiting TGF-β signaling in the tumor microenvironment could augment the efficacy of anti-CTLA-4 antibody therapy in a murine transgenic model of melanoma. Methods: Upon primary melanoma development in Tyr::CreER;BrafCA/+;PTENlox/loxmice, the LY2157299 type I TGF-β receptor serine/threonine kinase inhibitor was administered daily by oral gavage accompanied by intra-peritoneal delivery of anti-CTLA-4 monoclonal antibody (mAb) every three days. Tumor development was monitored by caliper and photodocumentation/imaging analysis. After 14 days, tumor tissue, tumor-draining lymph node (TDLN) tissue, and lung tissue was re...