Combination of Sunitinib and PD-L1 Blockade Enhances Anticancer Efficacy of TLR7/8 Agonist-Based Nanovaccine.

Abstract

Cancer vaccines composed of tumor-associated antigens (TAAs) and toll-like receptor (TLR) agonists have shown promising antitumor efficacy in preclinical studies by generating antigen-specific CD8 T cells, but translation of cancer vaccines to the clinic has been limited due to variables responses and development of resistance. The tumor microenvironment deploys various immune escape mechanisms that neutralize CD8 T cell-mediated tumor rejection. Therefore, we hypothesized that modulation of the tumor microenvironment can augment CD8 T cell activation and enhance therapeutic efficacy of cancer vaccines. To accomplish this, we aimed to eliminate immune suppressive cells and block their inhibitory signaling. Combination of the tyrosine kinase inhibitor (TKI) sunitinib with a nanoparticle-based cancer vaccine (nanovaccine) resulted in the reduction of immune-suppressive myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs). Blockade of programmed death-ligand 1 (PD-L1) using anti-PD-L1 antibody was used to reduce CD8 T cell exhaustion. Combination of nanovaccine+sunitinib+PD-L1 antibody treatment reduced PD-L1high M2 macrophages and MDSCs and upregulated activation of CD8 T cells in the tumor. Nanovaccine+sunitinib+PD-L1 antibody treatment also stimulated antigen-specific CD8 T cell response, which led to improved therapeutic efficacy in MB49 and B16F10 murine tumor models. These results suggest that modulation of tumor microenvironment using sunitinib and PD-L1 blockade can significantly enhance the antitumor efficacy of cancer nanovaccine.