Abstract 3465: HDAC8 regulates immune escape in melanoma through increased transcription of inhibitory cytokines that increase accumulation of myeloid-derived suppressor cells (MDSCs)

Abstract Immune checkpoint blockade leads to improved and durable responses in 30-40% of melanoma, yet nearly 1/3 of patients relapse from complete remission within 3 years. Recent studies from our group and others demonstrated that upfront use of targeted therapy leads to decreased immune infiltrate and confers resistance to immunotherapy. We have previously showed that HDAC8 reprograming cell transcriptional states leads to reduced recognition by immune system. However, it’s unclear how HDAC8 activity modulates the tumor immune microenvironment (TIME). In this study, we used integrated single cell RNA-seq, ATAC-seq and a novel BRAF-V600E; PTEN+/- melanoma genetically engineered mouse model (GEMM) to explore “cold” TIME modulated by HDAC8. Analysis of human melanoma cells overexpressing HDAC8 by ATAC-seq, ChIP-Seq and RNA-Seq showed that HDAC8 expression significantly increases chromatin accessibility, H3K27 promoter region acetylation and gene expression of IL-11. Increased IL-11 protein expression was confirmed by cytokine array in isogenic SM1 mouse melanoma cells expressing HDAC8.Overexpression of HDAC8 in the GEMM accelerated melanoma development and was associated with worse overall survival rate. Analysis of HDAC8 and control tumors by scRNA-seq and immunohistochemistry (IHC) showed that HDAC8 overexpressing tumors dramatically decreased CD4 and CD8 T cell infiltration and increased MDSCs and IL-11 expression. We next explored whether IL-11 drives the expansion and polarization of MDSCs and subsequent reduction in T cell infiltration and activation. A MDSCs polarization assay demonstrated that addition of IL-11 led to increased expansion and polarization of MDSCs from mouse bone marrow myeloid cells. A MDSCs suppression assay confirmed IL-11 induced MDSCs accumulation significantly reduced T cell proliferation and activation. We show for the first time that HDAC8 expression regulates immune escape by activating IL-11 expression and driving MDSCs expansion. Going forward, inhibition of HDAC8 activity is intriguing as a novel therapeutic strategy to reverse tumor derived immune suppression and to ultimately improve patient responses to immunotherapy. Citation Format: Chao Zhang, Michael Emmons, Richard Bennett, Jonathan Licht, Keiran Smalley. HDAC8 regulates immune escape in melanoma through increased transcription of inhibitory cytokines that increase accumulation of myeloid-derived suppressor cells (MDSCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3465.