IDDF2019-ABS-0174 Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma
| Autor: | Stephen L. Chan, John Wong, Hanyong Sun, Anthony W.H. Chan, Weiqin Yang, Philip Chun Yeung, Man Liu, Jingying Zhou, Ka Fai To, Zhiwei Chen, Alfred S. L. Cheng, Minhu Chen, Jie Chen, Hongchuan Jin, Joseph J.Y. Sung, Yu Feng, Otto Ka-Wing Cheung, Xiaoyu Liu, Xuezhen Zeng, Feng Wu, Myth Tsz Shun Mok, Paul B.S. Lai, Wenshu Tang |
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| Rok vydání: | 2019 |
| Předmět: |
medicine.diagnostic_test
business.industry medicine.medical_treatment Monocyte Immunosuppression Immunotherapy medicine.disease Peripheral blood mononuclear cell Flow cytometry Immunosurveillance medicine.anatomical_structure Hepatocellular carcinoma Hepatic stellate cell Cancer research Medicine business |
| Zdroj: | Gut – IDDF Young Investigator Award. |
| DOI: | 10.1136/gutjnl-2019-iddfabstracts.4 |
| Popis: | Background Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune-checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy. Methods Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet, and verified by clinical specimens. Mechanistic studies were conducted in the human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically-trialed BET bromodomain inhibitor i-BET762 was determined. Results Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumor-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumor-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumor phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signaling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumor eradication and prolonged survival in the fibrotic-HCC mouse model. Conclusions Our results signify how non-tumor intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy (figure 1). Acknowledgement This project is supported by the University Grants Committee through the Collaborative Research Fund (C4045–18W) and the Theme-based Research Scheme (T11–706/18-N), the Health and Medical Research Fund (16170451), the Terry Fox Foundation, the Focused Innovations Scheme-Scheme B (1907309) from the Chinese University of Hong Kong and the Li Ka Shing Foundation (Canada). Man Liu is supported by China Postdoctoral Science Foundation. |
| Databáze: | OpenAIRE |
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