دورية أكاديمية
Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells
| العنوان: | Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells |
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| المؤلفون: | Mastelic-Gavillet, Beatris, Navarro Rodrigo, Blanca, Décombaz, Laure, Wang, Haiping, Ercolano, Giuseppe, Ahmed, Rita, Lozano, Leyder Elena, Ianaro, Angela, Derré, Laurent, Valerio, Massimo, Tawadros, Thomas, Jichlinski, Patrice, Nguyen-Ngoc, Tu, Speiser, Daniel E., Verdeil, Grégory, Gestermann, Nicolas, Dormond, Olivier, Kandalaft, Lana, Coukos, George, Jandus, Camilla, Ménétrier-Caux, Christine, Caux, Christophe, Ho, Ping-Chih, Romero, Pedro, Harari, Alexandre, Vigano, Selena |
| المصدر: | Journal for ImmunoTherapy of Cancer 7(1) 257 |
| سنة النشر: | 2019 |
| المجموعة: | Zenodo |
| مصطلحات موضوعية: | Adenosine, CD8 T cells, Metabolism, mTOR, TILs |
| الوصف: | Background: Several mechanisms are present in the tumor microenvironment (TME) to impair cytotoxic T cell responses potentially able to control tumor growth. Among these, the accumulation of adenosine (Ado) contributes to tumor progression and represents a promising immunotherapeutic target. Ado has been shown to impair T cell effector function, but the role and mechanisms employed by Ado/Ado receptors (AdoRs) in modulating human peripheral and tumor-infiltrating lymphocyte (TIL) function are still puzzling.Methods: CD8+ T cell cytokine production following stimulation was quantified by intracellular staining and flow cytometry. The cytotoxic capacity of tumor infiltrating lymphocytes (TILs) was quantified by the chromium release assay following co-culture with autologous or anti-CD3-loaded tumor cell lines. The CD8+ T cell metabolic fitness was evaluated by the seahorse assay and by the quantification of 2-NBDG uptake and CD71/CD98 upregulation upon stimulation. The expression of AdoRs was assessed by RNA flow cytometry, a recently developed technology that we validated by semiquantitative RT-PCR (qRT-PCR), while the impact on T cell function was evaluated by the use of selective antagonists and agonists. The influence of Ado/AdoR on the PKA and mTOR pathways was evaluated by phosphoflow staining of p-CREB and p-S6, respectively, and validated by western blot.Results: Here, we demonstrate that Ado signaling through the A2A receptor (A2AR) in human peripheral CD8+ T cells and TILs is responsible for the higher sensitivity to Ado-mediated suppression of T central memory cells. We confirmed that Ado is able to impair peripheral and tumor-expanded T cell effector functions, and we show for the first time its impact on metabolic fitness. The Ado-mediated immunosuppressive effects are mediated by increased PKA activation that results in impairment of the mTORC1 pathway.Conclusions: Our findings unveil A2AR/PKA/mTORC1 as the main Ado signaling pathway impairing the immune competence of peripheral T cells and TILs. ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | info:eu-repo/grantAgreement/EC/FP7/602200/; https://zenodo.org/communities/fp7-bmcTest; https://zenodo.org/record/3484176Test; https://doi.org/10.1186/s40425-019-0719-5Test; oai:zenodo.org:3484176 |
| DOI: | 10.1186/s40425-019-0719-5 |
| الإتاحة: | https://doi.org/10.1186/s40425-019-0719-5Test https://zenodo.org/record/3484176Test |
| حقوق: | info:eu-repo/semantics/openAccess ; https://creativecommons.org/licenses/by/4.0/legalcodeTest |
| رقم الانضمام: | edsbas.C23FDDCD |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s40425-019-0719-5 |
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