School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, China
Man Liu
Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
Haoran Wu
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Wenshu Tang
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Weiqin Yang
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Thomas T.H. Chan
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Lingyun Zhang
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Shufen Chen
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Zhewen Xiong
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Jianxin Liang
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Willis Wai-Yiu Si-Tou
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Ting Shu
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Jingqing Li
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Jianquan Cao
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
Chengpeng Zhong
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Hanyong Sun
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Tsz Tung Kwong
Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China
Howard H.W. Leung
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
John Wong
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
Paul Bo-San Lai
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
Ka-Fai To
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
Tingxiu Xiang
Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, China
Joseph Jao-Yiu Sung
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
Stephen Lam Chan
Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
Jingying Zhou
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Corresponding authors. Address: Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Alfred Sze-Lok Cheng
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Corresponding authors. Address: Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-β signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-β upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.
