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Project description:PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53 -/- HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53 -/- HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin-driven tumors were resistant to anti-PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion. SIGNIFICANCE: Determinants of response to anti-PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti-PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion.See related commentary by Berraondo et al., p. 1003.This article is highlighted in the In This Issue feature, p. 983.
| S-EPMC6677618 | biostudies-literature
Project description:β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma
| PRJNA515888 | ENA
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery. We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment.
2015-05-21 | E-GEOD-43619 | biostudies-arrayexpress
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC (GSE43619) and a mouse model.
2014-12-31 | GSE43628 | GEO
Project description:Background & Aims: Patients with beta-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) have demonstrated limited clinical benefit to first-line immunotherapy (IO). Animal models of HCC expressing mutant-beta-catenin and additional aberrations via hydrodynamic tail vein injection with sleeping beauty transposon/transposase (SB-HDTVI) represent clinically relevant human HCC subsets. Here, we perform transcriptomic analysis on multiple beta-catenin-mutated and non-mutated HCC animal models to identify Mutated beta-catenin Gene Signature (MBGS) for HCC patient stratification for CTNNB1-mutations and IO response. Methods: We co-expressed in mice mutant-NFE2L2 and hMET +- mutant-CTNNB1 via SB-HDTVI and monitored for HCC development. Bulk RNA-sequencing was assessed for transcriptional differences between various beta-catenin-mutated and non-mutated models. MBGS was generated for predictive ability of CTNNB1 mutations and IO resistance in multiple HCC patient cohorts. Results: Co-expression of S45Y-beta-catenin + G31A-NFE2L2 + hMet (beta-N-M) resulted in HCC development by 4.5 weeks while co-expression of G31A-NFE2L2 + hMet (N-M) led to HCC by 14 weeks with tumors being positive for expected targets by immunohistochemistry (IHC). Bulk RNA-sequencing comparing beta-catenin-driven versus non-beta-catenin driven models yielded 95 common upregulated genes. Differential gene expression analysis of the common genes comparing CTNNB1-mutated vs non-mutated TCGA patients narrowed the gene panel to 13-(or 10-) genes. This MBGS predicted CTNNB1-mutation status in TCGA (n=374) and French (n=398) patient cohorts (with ROC AUC of 0.90 and 0.94). High MBGS expression was also associated with no overall and progression-free survival benefit when comparing atezolizumab + bevacizumab versus sorafenib arms in IMbrave150 cohort implying fewer treatment effects. Conclusions: In an era of patient molecular stratification for HCC, MBGS may aid in optimally selecting patients for IO through diagnosis of a molecular subset which lacks optimal response.
2024-10-09 | GSE261316 | GEO
Project description:We screened HCC organoids to identify a CTNNB1-mutant HCC selective small molecule (WNTinib), with MOA depending on reactivation of cytoplasmic EZH2, leading to its nuclear translocation and selective transcriptional block of WNT targets
2023-05-03 | GSE213515 | GEO
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery.
2015-05-21 | GSE43619 | GEO
Project description:We screened HCC organoids to identify a CTNNB1-mutant HCC selective small molecule (WNTinib), with MOA depending on reactivation of cytoplasmic EZH2, leading to its nuclear translocation and selective transcriptional block of WNT targets We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 genetically different organoids at 3 time points.
2023-05-03 | GSE213517 | GEO
Project description:The efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) treatment remains limited, warranting further investigation into the underlying mechanisms. Accumulating evidence indicates that myeloid cells within the tumor microenvironment (TME) play a role in immune evasion and treatment resistance. In this study, we aimed to explore the contribution of tumor-associated macrophages (TAMs) in the HCC TME. Our findings unveil the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Additionally, we identified prostaglandin E2 (PGE2) released by immune-attacked tumor cells as a key driver of CX3CR1+ TAM recruitment. To enhance the therapeutic response to current anti-PD-1 therapy, we propose a novel treatment strategy that combines targeted depletion of CX3CR1+ TAMs with anti-PD-1 therapy. Overall, our study contributes to the understanding of TAMs' role in cancer immunotherapy and presents potential clinical implications for HCC treatment. By targeting CX3CR1+ TAMs in conjunction with anti-PD-1 therapy, we have the potential to enhance the effectiveness of immunotherapeutic interventions in HCC patients.
2024-07-25 | GSE263240 | GEO
Project description:The combination of immune checkpoint blockade and tyrosine kinase inhibitors has shown promising clinical benefits, but the underlying mechanisms driving response and resistance are poorly understood. Here, we performed single-cell RNA- and TCR-sequencing, together with a HBV-peptide-barcoded single-cell RNA-sequencing approach, on paired tumor and blood samples to track the dynamic changes of T cells in HBV+ hepatocellular carcinoma (HCC) patients before or after anti-PD-1 plus lenvatinib combination therapy.
2024-12-17 | GSE235863 | GEO