β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma
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- Marina Ruiz de Galarreta
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Erin Bresnahan
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Pedro Molina-Sánchez
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Katherine E. Lindblad
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Barbara Maier
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Daniela Sia
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Marc Puigvehi
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Verónica Miguela
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- María Casanova-Acebes
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Maxime Dhainaut
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Carlos Villacorta-Martin
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Aatur D. Singhi
- 6Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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- Akshata Moghe
- 6Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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- Johann von Felden
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Lauren Tal Grinspan
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Shuang Wang
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Alice O. Kamphorst
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Satdarshan P. Monga
- 6Division of Experimental Pathology, Department of Pathology, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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- Brian D. Brown
- 3The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Augusto Villanueva
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Josep M. Llovet
- 2Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Miriam Merad
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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- Amaia Lujambio
- 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
抄録
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>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.</jats:p> <jats:p>See related commentary by Berraondo et al., p. 1003.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 983</jats:p> </jats:sec>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 9 (8), 1124-1141, 2019-08-01
American Association for Cancer Research (AACR)