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Squalene cyclooxygenase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in regulating the tumor immune microenvironment in MASH-HCC is unclear.
2024年5月14日，香港中文大学于君团队在Gut（IF 25）在线发表题为“Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma”的研究论文，该研究靶向角鲨烯环氧化酶在代谢功能障碍相关的脂肪性肝炎诱导的肝细胞癌中恢复抗PD-1的功效。 与野生型小鼠相比，肝细胞特异性Sqle tg小鼠的MASH-HCC.负荷显著增加，肿瘤浸润功能IFN-γ +和颗粒酶B+ CD8+ T细胞减少，而Arg-1+髓源性抑制细胞(MDSCs)富集。 相反，肝细胞特异性敲除SQLE抑制肿瘤生长，细胞毒性CD8+ T细胞增加，Arg-1+ MDSCs减少，推断SQLE促进MASH-HCC的免疫抑制。
Mechanistically, the accumulation of SQLE-driven cholesterol in the tumor microenvironment underlies its effects on CD8+ T cells and MDSCs. SQLE and its metabolite cholesterol impairs CD8+ T cell activity by inducing mitochondrial dysfunction. In vitro cholesterol removal abolishes the effects of SQLE-overexpressing MASH-HCC cell supernatants on CD8+ T cell inhibition and MDSC activation, while cholesterol supplementation has a very different effect on CD8+ T cells and SQLE-knockout supernatant-treated MDSCs. Gene ablation or the drug inhibitor terbinafine-targeted SQLE may rescue the efficacy of anti-PD-1 therapy in the MASH-HCC model. Therefore, SQLE induces impaired anti-tumor responses to MASH-HCC by attenuating CD8+ T cell function and enhancing immunosuppressive MDSCs. SQLE is a promising target to promote anti-PD-1 immunotherapy for MASH-HCC.
Metabolic dysfunction-associated steatosis liver disease (MASLD) is considered a hepatic manifestation of metabolic syndrome, affecting more than 25% of adults worldwide and showing a rapid upward trend Some MASLD patients develop metabolic dysfunction-associated steatohepatitis (MASH), a severe form of MASLD that can progress to cirrhosis and hepatocellular carcinoma (HCC). MASLD is an emerging risk factor for HCC, particularly in developed societies, where the pathogenesis of MASH-HCC involves cascading events including lipotoxicity, chronic inflammation, liver fibrosis, and eventual tumorigenesis. However, there is no specific treatment for MASH-HCC, and there is an unmet need to effectively target MASH-HCC. In recent years, immune checkpoint inhibitors (ICIs) have emerged as one of the most promising strategies in cancer treatment. ICIs targeting programmed cell death protein 1 (PD-1) have been approved for the treatment of advanced HCC, with overall response rates ranging from 7% to 36%. In contrast to the responsiveness of virus-associated HCC to ICI therapy, whether MASH-HCC responds to ICI therapy remains far from established. Two studies have shown that MASH-HCC responds poorly to ICIs in both human patients and mouse models. At the same time, a recent meta-analysis of eight randomized controlled trials (RCTs) showed that non-viral HCC may benefit from ICIs-based treatments compared to virus-associated HCC, which has a unique tumor immune microenvironment (TIME) that accumulates depleted T cell subsets (CD8+ PD-1+), necessitating the development of molecular targets to improve the responsiveness of ICI therapy targeting this subset of HCC patients. However, the underlying mechanism of MASH-HCC immunosuppression timing is still poorly understood.
模式图（Credit: Gut）
Squalene cyclooxygenase (SQLE), as a rate-limiting enzyme for cholesterol synthesis, is the most upregulated metabolic gene in MASH-HCC patients. Previous work identified SQLE as an oncogenic agent of MASH-HCC by promoting HCC cell proliferation. However, it is unclear whether or how SQLE regulates the MASH time to facilitate MASH-hcc. The study explores the immunomodulatory role of SQLE in MASH-HCC and evaluates SQLE as a potential therapeutic target to enhance anti-PD-1 efficacy. The characterization of the immune landscape of liver-specific Sqle transgene (Sqle tg) and knockout mice carrying MASH-HCC suggests that Sqle impairs effective immune surveillance by inhibiting cytotoxic T cell function while inducing immunosuppressive activity in myeloid-derived suppressor cells (MDSCs). Mechanistically, it was demonstrated that SQLE enriches cholesterol in TIME, which in turn directly antagonizes effector T cells while activating MDSCs. The study found that targeting SQLE by gene knockout or re-use of the SQLE inhibitor (terbinafine) could restore the efficacy of anti-PD-1-based immunotherapy against MASH-HCC. In conclusion, tumor-intrinsic SQLE induces impaired antitumor monitoring of MASH-HCC through cholesterol accumulation in TIME, thereby disrupting tumor-infiltrating CD8+ T cell effector function and enhancing immunosuppressive MDSCs. Targeting SQLE is a potentially promising therapeutic strategy to reactivate cytotoxic T cells in response to anti-PD-1 therapy in MASH-HCC.
Original link https://doi.org/10.1136/gutjnl-2023-331117
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文章来源|“ iNature”
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