Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma

Gut. 2020 Feb;69(2):365-379. doi: 10.1136/gutjnl-2018-317257. Epub 2019 May 10.

Abstract

Objective: 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.

Design: 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 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 trialled 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 tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling 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 tumour eradication and prolonged survival in the fibrotic-HCC mouse model.

Conclusion: Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

Keywords: cancer immunobiology; fibrosis; hepatocellular carcinoma; immunotherapy; liver immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / therapy*
  • Cellular Reprogramming / immunology
  • Cyclopropanes / pharmacology
  • Cyclopropanes / therapeutic use
  • Hepatic Stellate Cells / immunology
  • Humans
  • Immune Tolerance
  • Immunotherapy / methods*
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / etiology
  • Liver Neoplasms / immunology
  • Liver Neoplasms / therapy*
  • Liver Neoplasms, Experimental / etiology
  • Liver Neoplasms, Experimental / immunology
  • Liver Neoplasms, Experimental / pathology
  • Liver Neoplasms, Experimental / therapy
  • Male
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Myeloid-Derived Suppressor Cells / immunology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Signal Transduction / physiology
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • 6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide
  • B7-H1 Antigen
  • CD274 protein, human
  • Cyclopropanes
  • Protein Kinase Inhibitors
  • Pyridines
  • p38 Mitogen-Activated Protein Kinases