A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment
| Autor: | Laura Conforti, Michael J. Arnold, Hannah S. Newton, Trisha Wise-Draper, Julianne Qualtieri, Andras Balajthy, Ameet A. Chimote, Péter Hajdu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Adenosine monophosphate Adenosine Adenosine A2 Receptor Agonists Receptor Adenosine A2A T cell Gene Expression CD8-Positive T-Lymphocytes Biochemistry Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Movement Phenethylamines Tumor Microenvironment medicine Humans Cytotoxic T cell Elméleti orvostudományok Receptor Molecular Biology Cells Cultured Aged Chemistry Chemotaxis Cell Biology Orvostudományok Middle Aged Intermediate-Conductance Calcium-Activated Potassium Channels medicine.disease Head and neck squamous-cell carcinoma Chemokine CXCL12 stomatognathic diseases 030104 developmental biology medicine.anatomical_structure Head and Neck Neoplasms 030220 oncology & carcinogenesis Carcinoma Squamous Cell Cancer research Female CD8 medicine.drug |
| Popis: | The limited ability of cytotoxic T cells to infiltrate solid tumors hampers immune surveillance and the efficacy of immunotherapies in cancer. Adenosine accumulates in solid tumors and inhibits tumor-specific T cells. Adenosine inhibits T cell motility through the A 2A receptor (A 2A R) and suppression of KCa3.1 channels. We conducted three-dimensional chemotaxis experiments to elucidate the effect of adenosine on the migration of peripheral blood CD8 + T cells from head and neck squamous cell carcinoma (HNSCC) patients. The chemotaxis of HNSCC CD8 + T cells was reduced in the presence of adenosine, and the effect was greater on HNSCC CD8 + T cells than on healthy donor (HD) CD8 + T cells. This response correlated with the inability of CD8 + T cells to infiltrate tumors. The effect of adenosine was mimicked by an A 2A R agonist and prevented by an A 2A R antagonist. We found no differences in A 2A R expression, 3′,5′-cyclic adenosine monophosphate abundance, or protein kinase A type 1 activity between HNSCC and HD CD8 + T cells. We instead detected a decrease in KCa3.1 channel activity, but not expression, in HNSCC CD8 + T cells. Activation of KCa3.1 channels by 1-EBIO restored the ability of HNSCC CD8 + T cells to chemotax in the presence of adenosine. Our data highlight the mechanism underlying the increased sensitivity of HNSCC CD8 + T cells to adenosine and the potential therapeutic benefit of KCa3.1 channel activators, which could increase infiltration of these T cells into tumors. |
| Databáze: | OpenAIRE |
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