A Selective Class I HDAC Inhibitor Recovers Intratumoral Interferon Signaling to Overcome Immune-checkpoint Blockade Resistance in Hepatocellular Carcinoma
Refereed conference paper presented and published in conference proceedings
CUHK Authors
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AbstractBackground Immune checkpoint blockade (ICB) therapies by antibodies have revolutionized the treatment paradigm for a variety of cancers. Although subsets of people exhibit durable responses, resistance and relapse are common in hepatocellular carcinoma (HCC).
Methods ICB resistant orthotopic-grafted murine models were established via serial selection of HCC cells in ICB-treated mice. Single-cell RNA-seq and single-cell multiomics, which enables simultaneous profiling of the transcriptome and chromatin landscape in the same single nuclei, were applied to decode the mechanisms underlying the ICB resistance and the epigenetic re-sensitization of ICB therapy, respectively. Multicolor flow cytometry was used to determine the immune profiles.
Results Using the established ICB-resistant murine models of HCC, our single-cell transcriptome analysis revealed that tumor-intrinsic interferon gamma (IFNγ) response was most significantly suppressed in ICB-resistant tumors, which was associated with decreased T cell activation and intratumoral infiltration. Moreover, we found that a novel specific class I histone deacetylase (HDAC) inhibitor CXD101 synergised with PD-(L)1 antibody to eradicate tumor and prolong survival in our resistant models, which was accompanied with enhanced intratumoral infiltration and activation of cytotoxic lymphocytes. Mechanistically, CXD101 combined with PD-L1 inhibition dramatically recovered the silenced tumor IFNγ pathway via enhancing the chromatin accessibility of key IFNγ responsive genes, thereby triggering antitumor immune responses.
Conclusions Our findings suggest that epigenetic corruption of tumorintrinsic IFNγ response may confer ICB resistance, which can be rectified by selective class I HDAC inhibition. Based on these findings, a Phase II clinical study of CXD101 plus anti-PD-1 on ICB-resistant patients has been registered for trial soon.
Methods ICB resistant orthotopic-grafted murine models were established via serial selection of HCC cells in ICB-treated mice. Single-cell RNA-seq and single-cell multiomics, which enables simultaneous profiling of the transcriptome and chromatin landscape in the same single nuclei, were applied to decode the mechanisms underlying the ICB resistance and the epigenetic re-sensitization of ICB therapy, respectively. Multicolor flow cytometry was used to determine the immune profiles.
Results Using the established ICB-resistant murine models of HCC, our single-cell transcriptome analysis revealed that tumor-intrinsic interferon gamma (IFNγ) response was most significantly suppressed in ICB-resistant tumors, which was associated with decreased T cell activation and intratumoral infiltration. Moreover, we found that a novel specific class I histone deacetylase (HDAC) inhibitor CXD101 synergised with PD-(L)1 antibody to eradicate tumor and prolong survival in our resistant models, which was accompanied with enhanced intratumoral infiltration and activation of cytotoxic lymphocytes. Mechanistically, CXD101 combined with PD-L1 inhibition dramatically recovered the silenced tumor IFNγ pathway via enhancing the chromatin accessibility of key IFNγ responsive genes, thereby triggering antitumor immune responses.
Conclusions Our findings suggest that epigenetic corruption of tumorintrinsic IFNγ response may confer ICB resistance, which can be rectified by selective class I HDAC inhibition. Based on these findings, a Phase II clinical study of CXD101 plus anti-PD-1 on ICB-resistant patients has been registered for trial soon.
All Author(s) ListYalin TU, Zhewen XIONG, Chengpeng ZHONG, Haoran WU, Jing WANG, Patrick Pak-Chun WONG, Weiqin YANG, Jiahuan LU, Jingying ZHOU, Ka-Fai TO, Joseph SUNG, Stephen Lam CHAN, David KERR, Nick La THANGUE, Alfred Sze-Lok CHENG
Name of ConferenceHong Kong Society for Immunology 2022 Scientific Meeting and Annual General Meeting
Start Date of Conference04/02/2023
End Date of Conference04/02/2023
Place of ConferenceCordis, Hong Kong
Country/Region of ConferenceHong Kong
Year2023
Month2
Day4
LanguagesEnglish-United States
