Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy.
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.
Paul A
PA
Beavis
Melissa A
MA
Henderson
Lauren
L
Giuffrida
Jane K
JK
Mills
Kevin
K
Sek
Ryan S
RS
Cross
Alexander J
AJ
Davenport
Liza B
LB
John
Sherly
S
Mardiana
Clare Y
CY
Slaney
Ricky W
RW
Johnstone
Joseph A
JA
Trapani
John
J
Stagg
Sherene
S
Loi
Lev
L
Kats
David
D
Gyorki
Michael H
MH
Kershaw
Phillip K
PK
Darcy
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*
D043705:Receptor, Adenosine A2A; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse