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β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma

ABSTRACT: β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma

PROVIDER: PRJNA515888 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8455630.fastq.gz	Fastqsanger.gz
	SRR8455640.fastq.gz	Fastqsanger.gz
	SRR8455631.fastq.gz	Fastqsanger.gz
	SRR8455641.fastq.gz	Fastqsanger.gz
	SRR8455632.fastq.gz	Fastqsanger.gz

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β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma

Project description:We study the role of CTNNB1 in immune escape in HCC.

2019-06-13 | GSE125336 | GEO

Extracellular vesicle based therapeutic targeting of b-catenin to modulate anti-cancer immune responses in Hepatocellular Cancer

Project description:Combination therapy with anti PD-1 and β -catenin siRNA delivered using biological nanoparticles provide an effective strategy for the treatment of Hepatocellular carcinoma.

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β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.

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.

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Blocking CX3CR1+ Tumor-associated Macrophages Synergize with anti-PD-1 Therapy in Hepatocellular Carcinoma

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.

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Proteomic analysis of HepG2 cells after mutated ß-catenin depletion

Project description:ß-catenin is a main oncogene in a large number of cancers (colorectal, liver, melanoma, uterus). Local immunosuppression induced by certain cancers remains a major problem of resistance to immunotherapies and its molecular mechanism remains poorly understood. Recently, ß-catenin mutated tumors (hepatocellular carcinoma (HCC) and melanoma) have been described as promoting immune evasion and resistance to anti-PD1 immunotherapy. Based on preliminary data obtained in HCC, we hypothesize that a defect in intercellular communication could be the cause of this immune evasion. The main objective of this project is to identify proteomic signatures of factors that can induce this immune escape in ß-catenin mutated HCC such as exosomes.

2024-07-08 | PXD043841 | Pride

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Project description:Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

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RNA-seq data for tumor and adjacent non-tumor tissues from hepatocellular carcinoma patients with anti-PD-1 therapy

Project description:Immune checkpoint inhibitors elicit durable antitumor effects in multiple cancers, yet not all patients respond. Here, we aimed to develop and validate a molecular classification of hepatocellular carcinoma (HCC) patients based on 42 fatty acid degradation genes and demonstrate its predictive ability in the clinical response of anti-PD1 therapy in HCC patients. We studied global mRNA expression profiles from 41 primary tumor tissues and 25 nontumor tissues derived from 41 HCC patients. 17 patients received anti-PD1 therapy and were available with clinical response. 63 samples were also sent for lipidomics analysis. Methods for the study included gene expression analysis, consensus clustering analysis, pathway enrichment analysis, and Single-Sample Gene Set Enrichment Analysis (ssGSEA). This study identified and validated a novel molecular classification based on fatty acid degradation that predicts clinical response to anti-PD-1 therapy in hepatocellular carcinoma.

2023-05-01 | GSE202069 | GEO

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Project description:Blocking CX3CR1+ Tumor-associated Macrophages Synergize with anti-PD-1 Therapy in Hepatocellular Carcinoma

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2023-02-01 | GSE220670 | GEO

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