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

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AbstractBackground: 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.
All Author(s) ListWeiqin 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
Name of ConferenceHong Kong Society for Immunology, 2019 Annual General Meeting and Scientific Meeting
Start Date of Conference12/10/2019
End Date of Conference12/10/2019
Place of ConferenceThe University of Hong Kong
Country/Region of ConferenceHong Kong
LanguagesEnglish-United States

Last updated on 2020-27-11 at 17:52