Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • 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
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • 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 Article has an altmetric score of 38

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 2

A2AR is upregulated on CAR T cells in vivo and limits their antitumor efficacy.

Options: View larger image (or click on image) Download as PowerPoint
A2AR is upregulated on CAR T cells in vivo and limits their antitumor ef...
C57BL/6-HER2 mice were injected with 1 × 106 24JK-HER2 (subcutaneous) (A) or 1 × 105 E0771-HER2 tumor cells (B and D–F). (A, B, D, and E) Mice were injected with 1 × 107 CAR T cells derived from WT or A2AR–/– splenocytes on days 7 and 8 after tumor injection following total-body irradiation (5 Gy) on day 7. Mice were injected with 50,000 IU IL-2 on days 0–4 after T cell transfer and, where indicated, with anti–PD-1 (200 μg/mouse) or 2A3 isotype control on days 0, 4, and 8 after T cell transfer. (C) 1 × 106 24JK-HER2 tumor cells were cocultured with 1 × 106 anti-HER2 CAR T cells for 48 hours in the presence of anti–PD-1 (50 μg/ml) or 2A3 isotype control. A further 1 × 106 24JK-HER2 tumor cells were added after 24 hours to provide chronic stimulation. Cells were lysed after 48 hours. Expression of A2AR is shown relative to T cells cocultured with 24JK parental tumor cells. (F) E0771-HER2 tumor–bearing mice were treated as above with Ly5.1+ CAR T cells. Nine days after T cell transfer, tumors and spleens of tumor-bearing mice were pooled, and CAR (Ly5.1+) and endogenous (CD45.2+) CD8+ T cells were FACS sorted. Expression of A2aR on these subsets was determined by qPCR in triplicate. (A, B, and D) Data are presented as the mean ± SEM of 6–8 mice from a representative experiment of n = 3. (C) Data are represented as the mean ± SD from a representative experiment of n = 2. (E) Survival endpoint was when tumor size reached >100 mm2. Data are shown for pooled experiments with n = 14–24 per group. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-way ANOVA (A, B, and D), 1-way ANOVA (C and F), or Mantel-Cox test (E).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Posted by 21 X users
Referenced in 24 patents
On 3 Facebook pages
Referenced in 1 Wikipedia pages
Reddited by 1
228 readers on Mendeley
See more details