Abstract 6402: Stress-induced HDAC8 reprogramming drives IL-11-mediated immune escape in melanoma
Authors: Michael F. Emmons, Chao Zhang, Zhihua Chen, Richard L. Bennett, Olga Vera, Manali S. Phadke, Kanchan Gupta, Florian A. Karreth, Jonathan D. Licht, Keiran S. Smalley
Journal: Cancer Research (2025)

Abstract Background: Immunotherapy has revolutionized melanoma treatment, with durable responses achieved in 30-40% of patients. However, nearly one-third of patients relapse within three years, highlighting the need to elucidate mechanisms of de novo and acquired resistance to immune checkpoint inhibitors. Histone deacetylase 8 (HDAC8) has been shown to transcriptionally reprogram melanoma cells, leading to resistance to targeted therapy and suppression of immune recognition pathways. Objectives: We investigated the role of HDAC8 in modulating the immune microenvironment and its impact on melanoma progression and resistance to immunotherapy. Methods: A BRAF-V600E; PTEN+/-, HDAC8-inducible genetically engineered mouse model (GEMM) was developed to study HDAC8’s role in melanomagenesis and immune modulation. Tumors were analyzed using single-cell RNA sequencing (scRNA-seq) and multiplexed immunofluorescence to evaluate immune infiltration and cytokine expression. Chromatin accessibility, histone modifications, and transcriptional changes were assessed in human melanoma cells overexpressing HDAC8 using ATAC-seq, ChIP-seq, and RNA-seq. Cytokine arrays, immunohistochemistry (IHC), and functional assays were employed to evaluate IL-11 expression and its effects on myeloid-derived suppressor cells (MDSCs) and T cell interactions. Results: HDAC8 overexpression in GEMMs accelerated melanomagenesis and significantly reduced overall survival. scRNA-seq and multiplexed immunofluorescence revealed decreased IFNG expression, reduced infiltration of CD4+ and CD8+ T cells, and increased accumulation of MDSCs in HDAC8-expressing tumors. In human melanoma cells, HDAC8 overexpression led to increased chromatin accessibility, H3K27 acetylation at promoter regions, and upregulation of IL-11 gene expression. These findings were validated using cytokine arrays in isogenic SM1 mouse melanoma cells and IHC of GEMM tumor samples. IL-11 overexpression was associated with a reduced immunotherapy response, an increase in MDSC accumulation, and reduced CD8+ and CD4+ T cell infiltration. A MDSC polarization assay demonstrated that IL-11 enhanced the expansion and polarization of MDSCs from mouse bone marrow myeloid cells. Co-culture of IL-11-conditioned MDSCs suppressed T cell proliferation in vitro. Furthermore, HDAC8 overexpression in melanoma cells impaired their recognition and killing by tumor-specific CD8+ T cells. Conclusions: HDAC8 promotes a "cold" immune microenvironment by increasing IL-11 expression, which drives MDSC accumulation and suppresses T cell recognition and infiltration. These effects contribute to reduced immunotherapy efficacy. Targeting HDAC8 or IL-11 represents a promising therapeutic strategy to reverse tumor-driven immune suppression and enhance patient responses to immunotherapy in melanoma. Citation Format: Michael F. Emmons, Chao Zhang, Zhihua Chen, Richard L. Bennett, Olga Vera, Manali S. Phadke, Kanchan Gupta, Florian A. Karreth, Jonathan D. Licht, Keiran S. Smalley. Stress-induced HDAC8 reprogramming drives IL-11-mediated immune escape in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6402.