Overcoming Resistance to Immune Checkpoint Blockade Therapy

ICB therapy is based on reactivating exhausted T-cells (PD-1) and increasing T-cell activation (CTLA-4), one major mechanism of resistance is mediated through downregulation of the Major Histocompatibility Complex I (MHC-I) on cancer cells, as the MHC complex is responsible for presenting antigen to T-cells, and thereby crucial for facilitating T-cell mediated killing. Another major significant avenue for ICB therapy resistance is the establishment of an immunosuppressive tumor immune microenvironment. Here we show evidence that by altering epigenetic regulation using a histone deacetylase inhibitor we can simultaneously increase MHC-I expression on tumor cells and change the differentiation of infiltrating immune cells from immunosuppressive macrophages towards immunostimulatory antigen presenting cells (APCs). Next, we present evidence that a small molecule inhibitor selective for the β-isoform of the molecular chaperone HSP90 also synergizes with ICB therapy, by inducing a type-I interferon response in cancer cells. Lastly, we provide strategies to target immunosuppressive neutrophils in cancer, which can be used to augment ICB therapies in a clinical setting. Our findings elucidate potential novel approaches towards improving the efficacy of immunotherapy in the treatment of cancers.