ß-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.
Cancer Discov
; 9(8): 1124-1141, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31186238
ABSTRACT
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 ß-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that ß-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, ß-catenin-driven tumors were resistant to anti-PD-1. In summary, ß-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 ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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Evasão Tumoral
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Resistencia a Medicamentos Antineoplásicos
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Beta Catenina
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Neoplasias Hepáticas
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Discov
Ano de publicação:
2019
Tipo de documento:
Article