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A new Northwestern Medicine study has uncovered how a key immunoregulatory receptor plays an unexpected dual role in promoting T-cell exhaustion during chronic infection and cancer, according to findings published in the Proceedings of the National Academy of Sciences. The research sheds light on why targeted cancer therapies have shown limited efficacy in recent clinical trials for a variety of solid tumors, according to Bin Zhang, MD, Ph.D., the Johanna Dobe Professor of Cancer Immunology and senior author of the study.
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"This discovery really challenges the traditional view of this emerging immune checkpoint molecule, the A2A receptor, as a purely linear immunosuppressive checkpoint. It actually uncovers a complex, context-dependent dynamic where too much or too little receptor activity drives T-cells toward a terminal dysfunctional state over time," said Zhang, who is also a professor of medicine in the Division of Hematology and Oncology, Microbiology-Immunology and Pathology.
CD8+ T-cells, a pillar of the body's adaptive immune response, are immune cells that patrol the body for pathogens, including viruses and bacteria, and conduct tumor surveillance.
In chronic viral infection and cancer, CD8+ T-cells undergo sustained T-cell receptor stimulation and inflammatory stress, which over time contributes to T-cell exhaustion.
The adenosine A2A receptor (A2AR) is a key immunoregulatory receptor that serves as an "immunosuppressive brake" by suppressing T-cell function in response to increased levels of the signaling molecule adenosine in inflamed or hypoxic microenvironments.
While A2AR-targeted therapies have been a focus of recent cancer clinical trials, they have shown limited efficacy in several cancers, including metastatic castration-resistant prostate cancer and renal cell carcinoma.
In the current study, Zhang's team aimed to better understand A2AR's role in CD8+ T-cell differentiation and cell fate decisions in chronic infection and cancer.
To their surprise, they discovered that A2AR plays a dual role in influencing CD8+ T-cell fate: Both sustained A2AR expression and loss of A2AR independently drive CD8+ T-cells to terminal exhaustion through distinct signaling pathways.
Using single-cell multiomics profiling, the scientists found that A2AR deficiency activates CD122 protein–dependent signaling to drive T-cell exhaustion. Simultaneously, they found that genetically deleting the CD122 protein in A2AR-deficient CD8+ T-cells in mouse models reduced terminal exhaustion, suggesting CD122 signaling is a key mediator of A2AR loss–driven exhaustion.
The findings reveal a paradoxical role for A2AR in shaping CD8+ T-cell fate during chronic infection and cancer and highlight the need for new therapeutic strategies that fine-tune, rather than merely inhibit, immune regulatory pathways to improve treatment outcomes.
"We hope this has a huge impact in that we can reconsider A2AR blockade strategies to improve the design of clinical trials. That's something we're really looking forward to in the next stage of this work," Zhang said.
More information: Longzhen Song et al, Sustained A2AR expression and loss paradoxically promote CD8 + T cell exhaustion, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2602385123
Provided by Northwestern University
This story was originally published on Medical Xpress.
