Research ArticleCell Biology

A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment

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Science Signaling  24 Apr 2018:
Vol. 11, Issue 527, eaaq1616
DOI: 10.1126/scisignal.aaq1616

Reduced K+ channel activity curbs T cell migration

T cell accumulation in solid tumors is limited by multiple factors found within the tumor microenvironment, including the nucleoside adenosine. Chimote et al. analyzed the migration of CD8+ T cells in a 3D chemotaxis assay and found that adenosine inhibited the chemotaxis of T cells from cancer patients more than T cells from healthy donors. The increased sensitivity of patient CD8+ T cells to adenosine correlated with reduced KCa3.1 potassium (K+) channel activity, but not adenosine receptor expression or signaling. Treatment with a KCa3.1 channel agonist restored patient CD8+ T cell migration in the presence of adenosine, suggesting that K+ channel activators may help augment T cell infiltration of adenosine-rich solid tumors.


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 A2A receptor (A2AR) 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 A2AR agonist and prevented by an A2AR antagonist. We found no differences in A2AR 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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