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.
| Original language | English |
|---|---|
| Pages (from-to) | 929-941 |
| Number of pages | 13 |
| Journal | Journal of Clinical Investigation |
| Volume | 127 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Mar 2017 |
Cite this
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Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. / Beavis, Paul A.; Henderson, Melissa A.; Giuffrida, Lauren; Mills, Jane K.; Sek, Kevin; Cross, Ryan S.; Davenport, Alexander J; John, Liza B; Mardiana, Sherly; Slaney, Clare Y.; Johnstone, Ricky W; Trapani, Joseph A.; Stagg, John; Loi, Sherene; Kats, Lev; Gyorki, David E; Kershaw, Michael H.; Darcy, Phillip K.
In: Journal of Clinical Investigation, Vol. 127, No. 3, 01.03.2017, p. 929-941.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy
AU - Beavis, Paul A.
AU - Henderson, Melissa A.
AU - Giuffrida, Lauren
AU - Mills, Jane K.
AU - Sek, Kevin
AU - Cross, Ryan S.
AU - Davenport, Alexander J
AU - John, Liza B
AU - Mardiana, Sherly
AU - Slaney, Clare Y.
AU - Johnstone, Ricky W
AU - Trapani, Joseph A.
AU - Stagg, John
AU - Loi, Sherene
AU - Kats, Lev
AU - Gyorki, David E
AU - Kershaw, Michael H.
AU - Darcy, Phillip K.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015877195&partnerID=8YFLogxK
U2 - 10.1172/JCI89455
DO - 10.1172/JCI89455
M3 - Article
VL - 127
SP - 929
EP - 941
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
ER -