HDAC Inhibitors Induce HLA Class I Molecules through the SOX10–IRF1 Axis in Clear Cell Sarcoma Cells

Abstract

Although immune checkpoint inhibitors (ICIs) are an effective treatment for clear cell sarcoma (CCS), a rare melanocytic sarcoma with a poor prognosis, their efficacies are still limited. Therefore, a novel therapeutic strategy is required to improve the efficacy of ICIs. We previously reported that histone deacetylase (HDAC) inhibitors increased melanoma immunogenicity through the SOX10–IRF1 pathway and may improve the efficacy of ICIs for melanoma. We herein demonstrated that the inhibition of HDAC induced the expression of HLA class I molecules through IRF1 in CCS cells, similar to melanoma. The suppression of SOX10 by small interfering RNA (siRNA) induced the expression of HLA class I molecules. In addition, the isoform-specific inhibition of HDAC1/3 induced the expression of another IRF1 downstream molecule, PD-L1 in CCS cells in concert with the suppression of SOX10. Furthermore, the knockdown of IRF1 impaired the induction of PD-L1 expression in CCS cells. Therefore, the inhibition of HDAC1/3 has potential as a novel strategy to increase immunogenicity and as combination therapy with ICIs for CCS and melanoma.