Nanoparticle delivery of CDDO-Me remodels the tumor microenvironment and enhances vaccine therapy for melanoma.

Lipid-calcium-phosphate nanoparticle (NP) delivery of Trp2 peptide vaccine is one of the most effective vaccine strategies against melanoma. However, due to the immunosuppressive microenvironment in the tumor, the achievement of potent immune responses remains a major challenge. NP delivery systems provide an opportunity to deliver chemotherapy agent to modulate the tumor microenvironment (TME) and improve the vaccine activity. Anti-inflammatory triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a broad spectrum inhibitor of several signaling pathways that are important in both cancer cells and cells in the TME. Intravenous delivery of CDDO-Me using poly-lactic-glycolic-acid NP combination with subcutaneous Trp2 vaccine resulted in an increase of antitumor efficacy and apoptotic tumor tissue than Trp2 vaccine alone in B16F10 melanoma. There was a significant decrease of both Treg cells and MDSCs and a concomitant increase in the cytotoxic T-lymphocyte infiltration in TEM of the vaccinated animals. Also, CDDO-Me remodeled the tumor associated fibroblasts, collagen and vessel in TME, meanwhile, enhanced the Fas signaling pathway which could sensitize the tumor cells for cytotoxic T lymphocyte mediated killing. The combination of systemic induction of antigen-specific immune response using Trp2 nanovaccine and targeted modification of the TME with the NP delivered CDDO-Me offers a powerful combination therapy for melanoma.