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

  • Marina Ruiz de Galarreta
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Erin Bresnahan
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Pedro Molina-Sánchez
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Katherine E. Lindblad
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Barbara Maier
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 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.
  • 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.
  • Verónica Miguela
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • María Casanova-Acebes
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • Maxime Dhainaut
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 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.
  • 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.
  • 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.
  • 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.
  • Lauren Tal Grinspan
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 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.
  • Alice O. Kamphorst
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 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.
  • Brian D. Brown
    3The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 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.
  • 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.
  • Miriam Merad
    1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 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

  • Cancer Discovery

    Cancer Discovery 9 (8), 1124-1141, 2019-08-01

    American Association for Cancer Research (AACR)

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