Fibrous liver promotes an immunosuppressive environment to facilitate hepatocellular carcinoma (HCC) initiation. However, the underlying mechanisms of liver fibrosis-elicited immune evasion are poorly elucidated. Myeloid derived suppressor cells (MDSCs) play a key role in immunosuppression, leading to low responsiveness of immune checkpoint blockade (ICB). Emerging evidence highlights the pivotal role of enhancer remodeling in cell identity establishment and tumor immunity. Therefore, we aimed to determine whether enhancer remodeling participates in MDSC generation and aggressive HCC development in fibrous liver, and further explore the potential of enhancer inhibition in targeting MDSCs and improving efficacy of ICB in fibrotic HCC treatment.

By a mouse hepatoma cell Hepa1-6 orthotopic fibrotic HCC mouse model, we found that monocytic MDSC (M-MDSC) subset was also dramatically expanded in murine fibrous liver and positively correlated with increased hepatic tumorigenicity. Hepatic stellate cell (HSC), as key profibrogenic stromal cell, stimulated immunosuppressive M-MDSC generation from human peripheral blood mononuclear cells (PBMCs). Mechanistically, activated HSCs initiated p38 MAPK-mediated enhancer remodeling and triggered monocyte-to-M-MDSC identity shifting. Enhancer inhibition by a clinically-trialed drug iBET-762 disrupted HSC-M-MDSC crosstalk and abrogated M-MDSC generation and immunosuppressive functions. Notably, combination of iBET-762 with anti-PD-L1 antibody significantly induced tumor-infiltrating T lymphocytes, leading to tumor eradication and prolonged host survival in fibrosis-associated HCC model. As we also showed profound suppression of HCC patient-derived M-MDSCs by enhancer inhibition, our results delineate an enhancer deregulation mechanism for M-MDSC generation in fibrous liver environment, highlighting a promising therapeutic strategy of combined enhancer and immune-checkpoint targeting for desmoplastic tumors.

This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309.

Citation Format: Man Liu, Jingying Zhou, Alfred Sze Lok Cheng. Targeting M-MDSC intrinsic enhancer reprogramming enhances the efficacy of immune checkpoint therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1517.