HDACi Delivery Reprograms Tumor-infiltrating Myeloid Cells to Eliminate Antigen-loss Variants

Immune recognition of tumor-expressed antigens by cytotoxic CD8+ T lymphocytes is the foundation of adoptive T-cell therapy. However, therapy-induced selective pressure can sculpt the antigenicity of tumors resulting in the outgrowth of variants that have lost the target antigen. Interestingly, tumor relapse resulting from adoptive memory T cell transfer and boosting oncolytic viral vaccination can be prevented using Class I histone deacetylase inhibitor, MS-275. We demonstrate that concomitant drug delivery subverts the phenotype and suppressive function of tumor-infiltrating myeloid cells and reprograms them with the cytotoxic capacity to directly eliminate antigen-negative tumor cells. By enhancing the production of IFNγ within the tumor microenvironment, our data suggest that MS-275 modifies the local cytokine landscape in favor of antitumor myeloid cell polarization. Total RNA (n=4 per group) obtained from tumors subjected to gp33-specific Tm + VSV-gp33 +/- MS-275 compared to untreated control tumors.