Journal
SCIENCE SIGNALING
Volume 11, Issue 527, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaq1616
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Funding
- NIH [R01CA95286]
- Pilot grant from the UCCI
- Just-In-Time Core Grant from CCTST, University of Cincinnati
- Division of Hematology Oncology at the University of Cincinnati
- CCTST [1UL1TR001425-01]
- Campus Hungary Program [B2/1SZ/12351]
- National Excellence Program [TAMOP 4.2.4. A/2-11-1-2012-0001 B]
- Bolyai Janos Fellowship (Hungarian Academy of Sciences)
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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.
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