Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy
Paul A. Beavis, … , Michael H. Kershaw, Phillip K. Darcy
Paul A. Beavis, … , Michael H. Kershaw, Phillip K. Darcy
Published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):929-941. https://doi.org/10.1172/JCI89455.
View: Text | PDF
Research Article Immunology Oncology

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

  • Text
  • PDF
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.

Authors

Paul A. Beavis, Melissa A. Henderson, Lauren Giuffrida, Jane K. Mills, Kevin Sek, Ryan S. Cross, Alexander J. Davenport, Liza B. John, Sherly Mardiana, Clare Y. Slaney, Ricky W. Johnstone, Joseph A. Trapani, John Stagg, Sherene Loi, Lev Kats, David Gyorki, Michael H. Kershaw, Phillip K. Darcy

×

Figure 1

Stimulation of the CAR results in upregulation of the A2AR, which limits CAR T cell cytokine production.

Options: View larger image (or click on image) Download as PowerPoint
Stimulation of the CAR results in upregulation of the A2AR, which limits...
(A) 2 × 106 murine anti-HER2 CAR T cells were stimulated overnight with either anti-CD3 (0.5 μg/ml)/anti-CD28 (0.5 μg/ml), anti-CMYC tag (1:1,000), or an isotype control. (B) 1 × 106 CAR T cells were cocultured with 1 × 106 24JK or 24JK-HER2 tumor cells for 4 hours. (A and B) Stimulated cells were lysed and RNA isolated. Expression of A2aR and housekeeping gene L32 was determined by qPCR. (A) Data were normalized to unstimulated CAR T cells and are presented as the mean ± SEM of 4 individual experiments. (B) Data are presented as the mean ± SD from a representative experiment of n = 3. (C–F) 2 × 105 CAR T cells were cocultured with 1 × 105 24JK/24JK-HER2 (C and E) or E0771/E0771-HER2 (D and F) tumor cells in the presence or absence of NECA (1 μM) and SCH58261 (1 μM). Supernatants were collected after 16 hours and the cytokine concentration determined. Data are represented as mean ± SD of triplicates from a representative experiment of n = 4. “θ” indicates that the recorded value was above the maximum indicated on the graph. “LXSN T cells” refers to T cells transduced with the empty retroviral vector (LXSN) control. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA; NS, not significant.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts