A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression
| Autor: | Stephen M. Hatfield, Akio Ohta, Jorgen Kjaergaard, Michail V. Sitkovsky, Graham B. Jones |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adenosine Receptor Adenosine A2A medicine.medical_treatment T cell Immunology CD8-Positive T-Lymphocytes Immunotherapy Adoptive Article Immune tolerance Mice 03 medical and health sciences Cell Line Tumor Immune Tolerance Tumor Microenvironment medicine Animals Humans Immunology and Allergy Cytotoxic T cell Hypoxia Mice Knockout Tumor microenvironment Brain Neoplasms Chemistry Immunity Sarcoma Immunotherapy Adenosine A2 Receptor Antagonists Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Tumor Escape Cell culture Cancer research Female CD8 |
| Zdroj: | The Journal of Immunology. 201:782-791 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1700850 |
| Popis: | Tumor hypoxia–driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A2 adenosine receptors (A2R) on tumor-reactive effector T cells, but there remains a need for careful evaluation of the limiting factors and properties of A2R blockade–enabled antitumor immunity. In studies of A2AR and/or A2BR gene–deficient mice, we found that A2AR deletion—but not A2BR deletion—liberates endogenous CD8+ T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred A2AR−/−, A2BR−/−, or A2AR−/−/A2BR−/− tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by A2AR on CD8+ T cells. Treatment with A2AR antagonist mimicked A2AR gene deletion in adoptive T cell immunotherapy. This therapeutic benefit of targeting A2AR was independent of the anatomical location of tumor growth. The enhanced antitumor reactivity also led to the eradication of established intracranial tumors, which was associated with mouse survival and the maintenance of long-lasting, tumor-specific immunological memory. The blockade of the A2AR on adoptively transferred T cells by synthetic A2AR antagonist led to higher levels of IFN-γ secretion by tumor-infiltrating CD8+ T cells. These data clarify the mechanism of hypoxia-driven immunosuppression in the tumor microenvironment by A2AR on tumor-reactive CD8+ T cells and show that selective A2AR antagonists can be effective in improving the outcomes of T cell–based immunotherapies. Demonstration of the T cell dose dependency of tumor rejection points to a major limitation of current cancer immunotherapies, in which the presence of sufficient numbers of tumor-reactive T cells in a patient is not known. |
| Databáze: | OpenAIRE |
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