HDAC5 modulates PD-L1 expression and cancer immunity via p65 deacetylation in pancreatic cancer

Abstract

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal 5-year survival less than 10%. Most patients with PDAC exhibit poor response to single-agent immunotherapy. Multimodal therapies targeting mechanisms of resistance to immunotherapy are urgently needed. We found that the class IIa histone deacetylase (HDAC) member, HDAC5 is downregulated in multiple solid tumors and its level were associated with favorable prognosis in PDAC patients. Upregulated genes in patients harboring HDAC5 deletions were enriched in adaptive immune responses and lymphocyte-mediated immunity in The Cancer Genome Atlas (TCGA) pancreatic cancer dataset. Methods: Tissue microarray of pancreatic cancer were used to analysis the correlation between HDAC5 and PD-L1. RNA-seq, transcription factor motif analysis, drug screening and molecular biology assays were performed to identify the mechanism of HDAC5's repression on PD-L1. Allografts of pancreatic cancer in mouse were applied to test the efficiency of HDAC5 inhibition and anti-PD1 co-treatment. Results: HDAC5 regulated PD-L1 expression by directly interacting with NF-κB p65; this interaction was suppressed by p65 phosphorylation at serine-311. Additionally, HDAC5 diminished p65 acetylation at lysine-310, which is essential for the transcriptional activity of p65. Importantly, we demonstrated that HDAC5 silencing or inhibition sensitized PDAC tumors to immune checkpoint blockade (ICB) therapy in syngeneic mouse model and KPC mouse derived PDAC model. Conclusion: Our findings revealed a previously unknown role of HDAC5 in regulating the NF-κB signaling pathway and antitumor immune responses. These findings provide a strong rationale for augment the antitumor effects of ICB in immunotherapy-resistant PDAC by inhibiting HDAC5.

HDAC5 inhibits ovarian angiogenesis in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome

“…As a representative histone deacetylase, HDAC5-mediated deacetylation has shown critical effects on breast cancer management [40]. HDAC5induced p65 deacetylation participates in modulating cancer immunity and PD-L1 expression in pancreatic cancer [41]. Herein, in this study, we propose that HDAC5induced VEGFR2 deacetylation might be implicated in ovarian angiogenesis in PCOS.…”

Current insight into the regulation of PD-L1 in cancer

“…In prostate cancer, RelB, a major member of the NF-κB family, upregulates PD-L1 mainly by binding to the NF-κB element located in the promoter of PD-L1 [ 44 ]. Furthermore, knockdown of histone deacetylase 5 (HDAC5) results in notable activation of NF-κB signaling, thus significantly increasing PD-L1 expression in pancreatic cancer (PC) [ 45 ].…”

“…Transcription factors MYC ↑T-ALL [26], NSCLC [27] BRD4 ↑lymphomas and leukemia [26,30], OC [31] STAT3 ↑T cell lymphoma [37], BC [38], osteosarcoma [40], GC [41] STAT1 ↑CHL and PMBCL [33], melanoma [34], HNSCC [35] NF-κB ↑prostate cancer [44], PC [45] CKD5 ↑medulloblastoma [46], melanoma [32] HIF-1α ↑multiple cancers [47,48] [184]…”

The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention

“…Furthermore, it was reported that HDACs are involved in the transcriptional regulation of programmed death ligand-1 (PD-L1), which is a transmembrane protein that engages with PD-1 on immune cells to inhibit the antitumor immune response. HDAC5 was reported to regulate the expression of PD-L1 through direct interaction with NF-κB p65 and inhibition of HDAC5-sensitized tumor cells to immune checkpoint blockade [ 109 ]. The upregulation of histone acetylation at the PD-L1 gene was induced with HDACI treatment in melanomas cells, which increased the expression of PD-L1 and, in turn, blocked immune surveillance [ 110 ].…”