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.