Genome-Wide Histone Acetylation Underlies Tumor Intrinsic Immune Signaling Induced by Photothermal Therapy in Ovarian Cancer

Abstract Ovarian cancers (OCs) remain a lethal gynecological malignancy characterized by an immunosuppressive tumor microenvironment lacking effector lymphocytes. Thus, increasing tumor intrinsic immune signaling in OC remains a therapeutic goal for improving recruitment and activation of lymphocytes to the tumor microenvironment. A nanoparticle-based thermal treatment, Prussian blue nanoparticle photothermal therapy (PBNP-PTT), has shown strong antigen-specific lymphocyte recruitment to the tumor microenvironment through induction of immunogenic cell death in preclinical tumor models. Therefore, this study sought to determine the efficacy of PBNP-PTT in OC cell lines. We first demonstrate that PBNP-PTT induced tumor intrinsic immune signaling in OC cells and led to improved monocyte activation through tumor intrinsic proinflammatory cytokine release and presentation of damage-associated molecular patterns. Accompanying this intrinsic immunostimulatory effect, we report a novel epigenetic hallmark response to PBNP-PTT characterized by genome-wide H3K9 acetylation. Finally, increasing histone acetylation via histone deacetylase inhibition (Panobinostat) improved the tumor intrinsic immune signaling potential of PBNP-PTT. These findings indicate that PBNP-PTT activates the release of immunostimulatory factors in ovarian cancer cells alongside H3K9ac rewiring and suggests the potential of combining PBNP-PTT with HDACi to improve tumor intrinsic immune signaling in ovarian cancer.