Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy.
J Clin Invest
; 127(3): 929-941, 2017 Mar 01.
Article
en En
| MEDLINE
| ID: mdl-28165340
ABSTRACT
Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Recombinantes de Fusión
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Receptores de Antígenos de Linfocitos T
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Linfocitos T CD4-Positivos
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Linfocitos T CD8-positivos
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Receptor de Adenosina A2A
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Neoplasias Mamarias Experimentales
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Clin Invest
Año:
2017
Tipo del documento:
Article