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

Abstract

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.

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

“…We showed that OKI-179 also upregulated PD-L1 expression in B-cell lymphomas but not in primary B cells (Wang et al, 2019). Notably, OKI-179 exhibits potent inhibitory activities on HDAC 1, 2 and 3 (Wang et al, 2019), consistent with the notion that HDAC3 is a crucial repressor of PD-L1 transcription (Deng et al, 2019).…”

“…Pan-HDAC inhibitors, such as vorinostat, TSA and panobinostat, induce PD-L1 expression in B-cell lymphomas (Deng et al, 2019). Selective HDAC3 inhibitors (e.g., RGFP966) also upregulated PD-L1 expression because HDAC3 was shown to repress PD-L1 transcription in B-cell lymphomas (Deng et al, 2019). We showed that OKI-179 also upregulated PD-L1 expression in B-cell lymphomas but not in primary B cells (Wang et al, 2019).…”

“…In DLBCL cell lines, HDAC inhibitors (trichostatin A, sodium butyrate, apicidin and entinostat) induce MHC class I expression (Cycon et al, 2013). Valproic acid (class I HDAC inhibitor), romidepsin (HDAC1/2 inhibitor) or RGFP966 (HDAC3 inhibitor) upregulates MHC class I expression and costimulatory molecules, such as CD80 and CD86, in B-cell lymphomas (Deng et al, 2019). Histone deacetylation typically induces a closed chromatin state at the MHC class II promoters, resulting in downregulation of MHC class II in tumors.…”

“…Mocetinostat increases PD-L1 expression in multiple HL cell lines (Huang et al, 2018). Pan-HDAC inhibitors, such as vorinostat, TSA and panobinostat, induce PD-L1 expression in B-cell lymphomas (Deng et al, 2019). Selective HDAC3 inhibitors (e.g., RGFP966) also upregulated PD-L1 expression because HDAC3 was shown to repress PD-L1 transcription in B-cell lymphomas (Deng et al, 2019).…”

The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy

“…In 32 types of cancers analyzed, we only detected positive associations between PD-L1 and macrophages or T cell lineage markers in 21, showing that, in the other 11 types of cancers analyzed, major factors contributing to tumor PD-L1 induction were unrelated to the immune landscapes. In fact, besides being induced by immune landscapes, tumor PD-L1 might be regulated by many other biological processes, including chromosomal rearrangements, copy number alterations, oncogenic pathway dysregulation, and epigenetic modulation (47)(48)(49)(50). In addition, although our current work focuses on the prognostic value and the immune landscapes of PD-L1 + cancer cells, PD-L1 + host cells, particularly macrophages and dendritic cells, also play very important roles in promoting cancer progression (16)(17)(18).…”