Abstract A068: HDAC1 and HDAC3 inhibition decreases myeloid derived suppressor cell function through STAT3-mediated apoptosis

Abstract Myeloid derived suppressor cells (MDSCs) are key players in an immune-suppressed tumor microenvironment (TME) and significantly contribute to immune checkpoint inhibition (ICI) resistance, making them favorable targets for cancer immunotherapy. Our group and others have investigated MDSCs as a therapeutic targets to sensitize the TME to ICIs in breast cancer. We have reported that epigenetic reprogramming of MDSCs by inhibiting histone deacetylases (HDACs) 1 and 3 with Entinostat decreases MDSC immunosuppressive function and contributes to ICI response. However, a clear molecular mechanism of HDAC1/3 inhibition driving ICI response has yet to be understood. In breast intratumoral MDSCs, breast-to-lung metastatic MDSCs, and an MDSC-like cell line, we found that Entinostat decreases phosphorylation and activation of STAT3, a transcription factor shown to play a role in MDSC suppression of T cells. We hypothesized that Entinostat decreases MDSC suppression through modulation of the STAT3 pathway. Chromatin immunoprecipitation sequencing (ChIP-seq) of J774M, an MDSC-like cell line, treated with Entinostat revealed differential promoter binding by STAT3. KEGG pathways analyses of STAT3-bound promoters revealed significant enrichment of the Apoptosis pathway, of which Entinostat decreased STAT3 enrichment at the promoter of Mcl1, a protein in the Bcl2 family that normally prevents apoptosis and promotes survival in MDSCs. We also found that treatment of J774M cells with STAT3 inhibitors C188-9 and Stattic decreased cell proliferation and increased cell death. Our findings provide new evidence implicating a STAT3-mediated mechanism leading to decreased MDSC suppressive signaling and function upon HDAC 1/3 inhibition. These findings and planned studies may lead to a more complete understanding of the mechanism driving response in the combination therapy of Entinostat + ICIs, potentially informing development of more specific therapeutics for future preclinical studies and identification of biomarkers for clinical screening. Citation Format: Aaron G. Baugh, Edgar Gonzalez, Sabrina K. Zhong, Matthew B. Jacobo, Kaliya Acevedo, Jesse Kreger, Yingtong Liu, Adam L. MacLean, Evanthia T. Roussos Torres. HDAC1 and HDAC3 inhibition decreases myeloid derived suppressor cell function through STAT3-mediated apoptosis [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A068.