Details

Autor(en) / Beteiligte

• Ruiz de Galarreta, Marina
• Bresnahan, Erin
• Molina-Sánchez, Pedro
• Lindblad, Katherine E
• Maier, Barbara
• Sia, Daniela
• Puigvehi, Marc
• Miguela, Verónica
• Casanova-Acebes, María
• Dhainaut, Maxime
• Villacorta-Martin, Carlos
• Singhi, Aatur D
• Moghe, Akshata
• von Felden, Johann
• Tal Grinspan, Lauren
• Wang, Shuang
• Kamphorst, Alice O
• Monga, Satdarshan P
• Brown, Brian D
• Villanueva, Augusto
• Llovet, Josep M
• Merad, Miriam
• Lujambio, Amaia

Titel

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

Ist Teil von

• Cancer discovery, 2019-08, Vol.9 (8), p.1124-1141

Ort / Verlag

United States

Erscheinungsjahr

2019

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in 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 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. . .