Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells
| Autor: | Beatris Mastelic-Gavillet, Selena Vigano, Grégory Verdeil, Massimo Valerio, George Coukos, Haiping Wang, Rita Ahmed, Ping-Chih Ho, Laurent Derré, Nicolas Gestermann, Christine Ménétrier-Caux, Alexandre Harari, Camilla Jandus, Daniel E. Speiser, Blanca Navarro Rodrigo, Giuseppe Ercolano, Tu Nguyen-Ngoc, Patrice Jichlinski, Lana E. Kandalaft, Angela Ianaro, Leyder Elena Lozano, Pedro Romero, Christophe Caux, Thomas Tawadros, Olivier Dormond, Laure Décombaz |
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| Přispěvatelé: | Mastelic-Gavillet, B., Navarro Rodrigo, B., Decombaz, L., Wang, H., Ercolano, G., Ahmed, R., Lozano, L. E., Ianaro, A., Derre, L., Valerio, M., Tawadros, T., Jichlinski, P., Nguyen-Ngoc, T., Speiser, D. E., Verdeil, G., Gestermann, N., Dormond, O., Kandalaft, L., Coukos, G., Jandus, C., Menetrier-Caux, C., Caux, C., Ho, P. -C., Romero, P., Harari, A., Vigano, S. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cancer Research Adenosine medicine.medical_treatment Lymphocyte mTORC1 CD8-Positive T-Lymphocytes 0302 clinical medicine Neoplasms Tumor Microenvironment Immunology and Allergy Cytotoxic T cell Aged 80 and over Chemistry Adenosine/immunology Adenosine/metabolism Adult Aged CD8-Positive T-Lymphocytes/immunology CD8-Positive T-Lymphocytes/metabolism Cell Line Tumor Cyclic AMP-Dependent Protein Kinases/metabolism Disease Progression Female Humans Lymphocytes Tumor-Infiltrating/immunology Lymphocytes Tumor-Infiltrating/metabolism Mechanistic Target of Rapamycin Complex 1/metabolism Middle Aged Neoplasms/immunology Neoplasms/metabolism Primary Cell Culture Receptor Adenosine A2A/metabolism Signal Transduction/immunology Tumor Escape Tumor Microenvironment/immunology CD8 T cells Metabolism TILs mTOR lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Molecular Medicine Cyclic AMP-Dependent Protein Kinase Research Article Human Signal Transduction Receptor Adenosine A2A T cell Immunology Mechanistic Target of Rapamycin Complex 1 lcsh:RC254-282 03 medical and health sciences Lymphocytes Tumor-Infiltrating medicine Pharmacology Tumor microenvironment Immunotherapy TIL CD8-Positive T-Lymphocyte Cyclic AMP-Dependent Protein Kinases T cell cytokine production 030104 developmental biology CD8 T cell Cancer research Neoplasm CD8 |
| Zdroj: | Journal for Immunotherapy of Cancer, Vol. 7, No 1 (2019) P. 257 Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-16 (2019) Journal for Immunotherapy of Cancer Journal for immunotherapy of cancer, vol. 7, no. 1, pp. 257 |
| ISSN: | 2051-1426 |
| Popis: | 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. Thus, p-CREB and p-S6 may represent useful pharmacodynamic and efficacy biomarkers of immunotherapies targeting Ado. The effect of Ado on T cell metabolic fitness reinforces the importance of the adenosinergic pathway as a target for next-generation immunotherapy. Electronic supplementary material The online version of this article (10.1186/s40425-019-0719-5) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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