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Genome-wide histone acetylation underscores tumor intrinsic immune signaling induced by photothermal therapy in ovarian cancer

ABSTRACT: Ovarian cancer remains the most lethal gynecological malignancy with few durable responses to standard of care platinum-based chemotherapies and emerging immunotherapies. This poor response is attributed to the immunosuppressive tumor microenvironment which lacks effector lymphocytes necessary for tumor clearance. Therefore, increasing tumor intrinsic immune signaling remains a therapeutic goal for OC. One strategy for improved tumor intrinsic immune signaling relies on induction of tumor cell immunogenic cell death (ICD) features including tumor cell surface expression of Calreticulin and Hsp70 with concurrent release of immunostimulatory signals that activate innate and adaptive immune cells. The induction of ICD through a nanoparticle-based heat shock treatment, termed Prussian blue nanoparticle photothermal therapy (PBNP-PTT), has shown strong recruitment of antigen-specific lymphocytes to the tumor microenvironment in glioblastoma and neuroblastoma preclinical models. While the molecular signatures of ICD are well described, the epigenetic reprogramming during treatment-induced tumor intrinsic immune signaling remains unknown. Therefore, this study sought to determine the efficacy of PBNP-PTT heat shock in ovarian cancer and characterize epigenetic responses that accompany its induced tumor intrinsic immune signaling. We first demonstrate that PBNP-PTT activates tumor intrinsic immune signaling in ovarian cancer and leads to improved monocyte activation through tumor cell proinflammatory cytokine release and presentation of Calreticulin and Hsp70. Accompanying this intrinsic immunostimulatory effect, PBNP-PTT induces genome-wide chromatin accessibility via H3K9ac, which associates with chromatin remodeling and heat shock response genes. Lastly, we show targeting histone acetylation via histone deacetylase inhibition (Panobinostat) improves 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 through H3K9ac rewiring and suggests the potential of combination with HDACi to improve tumor intrinsic immune signaling in ovarian cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326102 | GEO | 2026/04/02

REPOSITORIES: GEO

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Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.

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Genome-wide histone acetylation underscores tumor intrinsic immune signaling induced by photothermal therapy in ovarian cancer

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