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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:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.
2025-05-02 | GSE270975 | GEO
Project description:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.
2025-05-02 | GSE290449 | GEO
Project description:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.
2025-05-02 | GSE270714 | GEO