PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma

Background & Aims Recent studies demonstrated the importance of fibrosis in promoting immunosuppressive liver microenvironment for hepatocellular carcinoma (HCC) aggressive growth and immune-checkpoint blockade (ICB) resistance, 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 HCC patients. 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 of HCC patients. Blocking of transforming growth factor-beta (TGF-β) signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-β up-regulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expressions 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 by 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 strategic 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-MDSC. The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict HCC growth and enhance ICB efficacy. PPP1R15A may also have a dual biomarker role in prognosis and ICB response prediction.