While the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells are commonly associated with patients' responses to treatment with anti-PD-1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 (HOXA5) and signal transducer and activator of transcription 3 (STAT3). Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both HOXA5 and STAT3. Indeed, knockdown of HOXA5 or STAT3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, HOXA5 and STAT3

were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system.

Citation Format: Chen Chen Jiang, Yu Fang Wang, Simonne Sherwin, Margaret Farrelly, Fen Liu, Xu Guang Yan, Amanda Croft, Tao Liu, Lei Jin, Xu Dong Zhang. Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2523.