HDAC3 Inhibition Upregulates PD-L1 Expression in B-Cell Lymphomas and Augments the Efficacy of Anti–PD-L1 Therapy

Programmed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway blockade is a promising therapy for the treatment of advanced cancers, including B-cell lymphoma. The clinical response to PD-1/PD-L1 immunotherapy correlates with PD-L1 levels on tumor cells and other cells in the tumor microenvironment. Hence, it is important to understand the molecular mechanisms that regulate PD-L1 expression. Here, we report that histone deacetylase 3 (HDAC3) is a crucial repressor of PD-L1 transcription in B-cell lymphoma. Pan-HDACs or selective HDAC3 inhibitors could rapidly increase histone acetylation and recruitment of bromodomain protein BRD4 at the promoter region of PD-L1 gene, leading to activation of its transcription. Mechanically, HDAC3 and its putative associated corepressor SMRT were recruited to the PD-L1 promoter by the transcriptional repressor BCL6. In addition, HDAC3 inhibition reduced DNA methyltransferase 1 protein levels to indirectly activate PD-L1 transcription. Finally, HDAC3 inhibition increased PD-L1 expression on dendritic cells in the tumor microenvironment. Combining selective HDAC3 inhibitor with anti-PD-L1 immunotherapy enhanced tumor regression in syngeneic murine lymphoma model. Our findings identify HDAC3 as an important epigenetic regulator of PD-L1 expression and implicate combination of HDAC3 inhibition with PD-1/PD-L1 blockade in the treatment of B-cell lymphomas.