A New Strategy to Boost the Efficacy of Melanoma Immune Checkpoint Inhibitor by Targeting HDAC4 to Modify the T-cell Inflamed Signature

Abstract ID 128681 Poster Board 056 Melanoma remains one of the difficult malignancies to treat, due to its ability to evade anti-tumor immune responses via employing tolerance mechanisms such as negative immune checkpoint molecules. While immune checkpoint inhibitors (ICIs) have been increasingly used to treat melanoma, a considerable number of patients do not respond to this treatment, indicating the development of resistance mechanisms such as intrinsic tumor characteristics and an immunosuppressive tumor microenvironment (TME). Multiple studies have documented that an inflamed TME increases the therapeutic efficacy of ICIs via upregulating the expression of the T-cell inflamed signature, a set of genes linked with dendritic cell and T-cell anti-tumor response. Notably, histone deacetylases (HDACs) are frequently deregulated in melanomas. In addition, it has been demonstrated that HDACs can modulate the transcription of PD-1/PD-L1, and other genes linked to immune evasion. The objective of our research was to examine the association between the T-cell inflamed signature and histone deacetylases (HDACs) in melanoma patients. The data were obtained by use of the cBioPortal for Cancer Genomics and were sourced from melanoma dataset: "Skin Cutaneous Melanoma (TCGA, Firehose Legacy) (n = 287)". The analysis was focused on the co-expression of T-cell inflamed signature genes and the HDAC family. The study revealed a negative correlation between the mRNA expression of HDAC4 and several T-cell inflamed signature genes, including PD-L1, LAG3, IDO1, TIGIT, ICOS, STAT1, IFNG, CD8A, CD4, IRF1, PRF1, GZMA, GZMB, GZMK, CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCR6, CMKLR1, NKG7, PSMB10, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DQA1, HLA-DRB1, and HLA-E. Furthermore, we observed a significant methylation of T-cell inflamed signature genes in the group exhibiting elevated HDAC4 expression. Consequently, their transcriptions were rescued in the group who had a low HDAC4 expression. Based on our findings, HDAC4 may negatively modulate TME and ICI efficacy in melanoma. Furthermore, our research suggested a new method of targeting a specific epigenetic change, which has implications for developing a novel therapeutic strategy. Specifically, we propose combining an HDAC4 inhibitor with ICIs to enhance their effectiveness in melanoma. Further studies are required to validate our results.