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Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma.

ABSTRACT: Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.

SUBMITTER: Kong X

PROVIDER: S-EPMC9257027 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveNatural killer (NK) cells play a critical role in the innate antitumor immune response. Recently, NK cell dysfunction has been verified in various malignant tumors, including hepatocellular carcinoma (HCC). However, the molecular biological mechanisms of NK cell dysfunction in human HCC are still obscure.MethodsThe expression of circular ubiquitin-like with PHD and ring finger domain 1 RNA (circUHRF1) in HCC tissues, exosomes, and cell lines was detected by qRT-PCR. Exosomes were isolated from the culture medium of HCC cells and plasma of HCC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit and then characterized by transmission electronic microscopy, NanoSight and western blotting. The role of circUHRF1 in NK cell dysfunction was assessed by ELISA. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the molecular mechanisms of circUHRF1 in NK cells. In a retrospective study, the clinical characteristics and prognostic significance of circUHRF1 were determined in HCC tissues.ResultsHere, we report that the expression of circUHRF1 is higher in human HCC tissues than in matched adjacent nontumor tissues. Increased levels of circUHRF1 indicate poor clinical prognosis and NK cell dysfunction in patients with HCC. In HCC patient plasma, circUHRF1 is predominantly secreted by HCC cells in an exosomal manner, and circUHRF1 inhibits NK cell-derived IFN-? and TNF-? secretion. A high level of plasma exosomal circUHRF1 is associated with a decreased NK cell proportion and decreased NK cell tumor infiltration. Moreover, circUHRF1 inhibits NK cell function by upregulating the expression of TIM-3 via degradation of miR-449c-5p. Finally, we show that circUHRF1 may drive resistance to anti-PD1 immunotherapy in HCC patients.ConclusionsExosomal circUHRF1 is predominantly secreted by HCC cells and contributes to immunosuppression by inducing NK cell dysfunction in HCC. CircUHRF1 may drive resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for patients with HCC.

Project description:BackgroundImmune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC.MethodThe level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP-ADO pathway amplified by HCC-macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts.ResultsHere, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP-adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance.ConclusionIn summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP-adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC.

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Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma.

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