Immune Receptor Plays Dual Role in Promoting T-cell Exhaustion in Cancer
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 findings shed 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, PhD, the Johanna Dobe Professor of Cancer Immunology and senior author of the study.
“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 towards a terminal dysfunctional state over time,” said Zhang, who is also a professor of Medicine in the Division of Hematology and Oncology, of Microbiology-Immunology and of 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, as well as lead tumor surveillance.
In the case of 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 therapy trials, they have shown limited efficacy in several cancers, including in 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 in that both sustained A2AR expression and the 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 as 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.
Weiguo Cui, PhD, professor of Pathology in the Division of Experimental Pathology, was a co-corresponding-author of the study.
Cui and Zhang are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the Center for Human Immunobiology.
This work was supported in part by National Institutes of Health grants CA290743, CA258857, AI148403 and CA290743; the Melanoma Research Alliance (MRA) Next Steps Grant; and Established Scholar Award.
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