HDACi Delivery Reprograms Tumor-Infiltrating Myeloid Cells to Eliminate Antigen-Loss Variants

Immune recognition of tumor-expressed antigens by cytotoxic CD8+ T cells is the foundation of adoptive T cell therapy (ACT) and has been shown to elicit significant tumor regression. However, therapy-induced selective pressure can sculpt the antigenicity of tumors, resulting in outgrowth of variants that lose the target antigen. We demonstrate that tumor relapse from ACT and subsequent oncolytic viral vaccination can be prevented using class I HDACi, MS-275. Drug delivery subverted the phenotype of tumor-infiltrating CD11b+ Ly6Chi Ly6G– myeloid cells, favoring NOS2/ROS secretion and pro-inflammatory genes characteristic of M1 polarization. Simultaneously, MS-275 abrogated the immunosuppressive function of tumor-infiltrating myeloid cells and reprogrammed them to eliminate antigen-negative tumor cells in a caspase-dependent manner. Elevated IFN-γ within the tumor microenvironment suggests that MS-275 modulates the local cytokine landscape to favor antitumor myeloid polarization through the IFN-γR/STAT1 signaling axis. Exploiting tumor-infiltrating myeloid cell plasticity thus complements T cell therapy in targeting tumor heterogeneity and immune escape. [Display omitted] •Tumor recurrence during adoptive T cell therapy is associated with antigen loss•Concomitant delivery of HDAC inhibitor MS-275 promotes sustained tumor regression•MS-275 polarizes tumor-infiltrating myeloid cells to directly kill antigen-loss variants•Intratumoral IFN-γ enhances antitumor function in tumor-infiltrating myeloid cells Nguyen et al. find that delivery of histone deacetylase inhibitor MS-275 in combination with adoptive cell therapy and oncolytic viral vaccination enhances intratumoral IFN-γ to functionally reprogram immunosuppressive tumor-infiltrating myeloid cells into cytotoxic effectors capable of eliminating antigen-loss variants and preventing tumor relapse.