Enhancer reprogramming by selective HDAC8 inhibition potentiates tumor remission and durable benefit by PD-L1 blockade
Refereed conference paper presented and published in conference proceedings


摘要Background: The heterogeneous responses to immune-checkpoint blockade (ICB) therapy e.g. anti-programmed death-ligand 1 (PD-L1) antibody are attributable to the complex interplay between a range of cancer-cell-autonomous cues and immunosuppressive tumor microenvironment. The insufficient T cell infiltration into non-inflamed tumors such as hepatocellular carcinoma (HCC) restricts the effectiveness of ICB to a minority of patients. Accumulating evidence underscore the fundamental importance of epigenetic regulation in tumor immune evasion. We have previously elucidated a critical role of histone deacetylase 8 (HDAC8) in hepatic carcinogenesis (Cancer Research 2015;75:4803-16). Here, we aim to investigate the immune-modulatory and anti-tumor effects of the pharmacological inhibition of HDAC8, a H3K27-specific isozyme, in preclinical HCC model.
Methods: The effect of HDAC8-specific inhibitor PCI-34051 on tumorigenicity was investigated in orthotopic HCC mouse models. Immune profiling in tumor microenvironment was determined by multi-color flow cytometry. The underlying mechanism was investigated by integrative epigenomics analysis. The anti-tumor efficacy of combined therapy with PCI-34051 and anti-PD-L1 antibody was further determined.
Results: PCI-34051 significantly suppressed tumorigenicity in immunocompetent but not immunodeficient mice, which was accompanied by increased effector T cell while decreased Treg cell tumor infiltration. Mechanistically, tumor-intrinsic HDAC8 epigenetically silenced chemokine CCL4 expression via H3K27 deacetylation at the enhancer to inhibit T cell infiltration to tumor. Furthermore, PCI-34051 dramatically improved the therapeutic efficacy of anti-PD-L1 checkpoint blockade, leading to eradication of large tumor. More importantly, HDAC8 and PD-L1 co-blockade resulted in long-term survival (more than 1 year) with induction of T cell memory responses.
Conclusions: Our finding delineates that selective chromatin modifications by HDAC8 can augment the therapeutic efficacy of PD-L1 blockade therapy to fully unleash T cell responses, leading to long-term remission of HCC. This study highlights a new isozyme-specific epigenetic strategy to delivering precision immunotherapy to HCC patients.
著者Weiqin YANG, Yu FENG, Jingying ZHOU, Otto K.W. CHEUNG, Feng WU, Zhiwu TAN, Liangliang XU, Hanyong SUN, Yuan TIAN, Stephen L. CHAN, Anthony W.H. CHAN, Zhiwei CHEN, Kevin Y.L. YIP, Ka-Fai TO, Joseph J.Y. SUNG, Alfred S.L. CHENG
會議名稱Hong Kong Society for Immunology, 2019 Annual General Meeting and Scientific Meeting
會議地點The University of Hong Kong

上次更新時間 2020-27-11 於 17:52