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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.

Summary: Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk-knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8+T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8+T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy.

Background: Both microwave ablation (MWA) and radiofrequency ablation (RFA) are commonly employed local ablation techniques for malignant liver tumors. However, comparative data on long-term results between these two techniques is scarce in the literature. Methods: This is a retrospective comparative study between MWA and RFA for hepatocellular carcinoma (HCC) using surgical approach. Results: The MWA group consisted of 26 patients while the RFA group consisted of 47 case-matched patients. The two groups were comparable, except patients were older and their platelet count was lower in the MWA group. The median follow-up period was 47.5 months in MWA group and 52.9 months in RFA group (p = 0.322). There was no difference in 5-year overall survival (MWA 73.1%, RFA 46.3%, p = 0.082) and 5-year disease free survival (MWA 13.8%, RFA 14.6%, p = 0.736). When a subgroup analysis of tumors ≥ 3.5 cm was performed, there were 16 patients in the MWA group and 21 patients in the RFA group, the 5-year overall and disease-free survival were MWA 75.0%, RFA 28.6% (p = 0.022) and MWA 25.0%, RFA 4.8% (p = 0.207), respectively. Conclusion: MWA is comparable to RFA for HCC in terms of long-term outcomes. For tumors ≥ 3.5 cm, MWA is associated with a better overall 5-year survival.

Foreign body penetration of the stomach is seldom encountered in general surgical practice. Liver abscess as a consequence of such occurrence has only been reported sporadically. We report three cases of liver abscesses due to direct penetration injury of the stomach by ingested foreign bodies. All three patients presented with clinical features of liver abscess without history of foreign body ingestion. All recovered with surgical treatment. Successful management relies on prompt recognition and early intervention as deaths have been reported due to missed or delayed diagnosis. The potential role of a minimally invasive approach in the management of this entity is also discussed.