525 Adenosine uptake through equilibrative nucleoside transporter-1 suppresses antitumor immunity by pyrimidine starvation
Bibliographic record
Abstract
Background Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine can signal through specific receptors or be transported across the cell membrane through nucleoside transporters. While adenosine receptors are known to regulate tumor immunity, the impact of adenosine transporters remains unknown. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Methods We used selective inhibitors and gene targeting approaches to study the role of ENT1 on tumor growth in vitro and in vivo. We performed flow cytometry and quantitative PCR to profile the immune tumor microenvironment. To study the effect of adenosine uptake via ENT1, we performed coculture assays and metabolomic analysis of activated human T cells in presence of adenosine and a selective ENT1 inhibitor. Results In vivo, we demonstrated that blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent anti-tumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells and significant upregulation of granzyme B, IFN-γ, IL-2, TNF-α and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages, and suppressed CCL17 production. ENT1-deficiency also significantly potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 following activation and blocking ENT1 enhanced their effector function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake in activated T cells inhibited the activity of phosphoribosylpyrophosphate synthetase (PRPS), thereby suppressing production of uridine 5′-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. Conclusions In summary, our study identified ENT1-mediated adenosine uptake as an important and previously unappreciated mechanism of adenosine-mediated immunosuppression via pyrimidine starvation that can be targeted to enhance antitumor T cell responses. Our findings have important implications on our interpretation of current adenosine-targeting agents in clinical trial and suggest ENT1 is a potential therapeutic target to enhance the therapeutic activity of immune checkpoint blockade. Ethics Approval Animal experimentations were performed in accordance with guidelines from the Canadian Council on Animal Care (CCAC) and were approved by an Institutional Animal Care and Use Committee (Protocol #C22051JSs).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".