Adenosine Inhibits T cell Tumor Infiltration: KCa3.1, a New Anticancer Target

By Yoskaly Lazo-Fernandez, PhD

Role of Adenosine in the Tumor Microenvironment a Target for Cancer Therapy

The tumor microenvironment (TME) tends to be concentrated in the purine nucleoside adenosine, a direct result of the hypoxia normally associated with cancer. Extracellular adenosine binds to its receptor, A_2A receptor (A_2AR), in the surface of lymphocytes and other immune cells resulting in anti-inflammatory and immunosuppressive responses¹ which correlate with higher tumor progression and poor prognosis in cancer patients². Extracellular adenosine accumulation in the TME has thus emerged as an inhibitory immune check point with great potential as a new avenue for cancer immunotherapy.

The potential of adenosine as a new therapeutic target has stimulated intense research on the molecular mechanisms of adenosine-mediated immunosuppression and on the effects of monoclonal antibodies or small chemicals inhibiting different targets of the hypoxia–adenosine pathway. Preclinical studies have shown that the inhibition of adenosine signaling, either by gene deletion or by pharmacological inhibition of the A_2AR and the ectonucleotidase CD73, reduces cancer load and stimulates the efficacy of immunotherapies in mice¹.

“If we are envisioning a therapy, then it must be something that is specifically directed towards the T lymphocytes, as KCa3.1 channels are everywhere. So, the mode of delivery has to be a targeted immunotherapy.”

Ameet A Chimote, PhD is a Research Associate in Dr. Laura Conforti’s laboratory at the Department of Internal Medicine, Division of Nephrology and Hypertension at the University of Cincinnati, Cincinnati OH. Dr. Conforti’s laboratory studies the role played by ion channels in regulating T lymphocyte function in cancers. Dr. Chimote studies the function of potassium channels and how their activity may impact lymphocyte activity in solid tumors of head and neck cancers.

How Adenosine Accumulates in the Tumor Microenvironment

Hypoxia is the first step in the adenosinergic pathway. It induces the accumulation of ATP in the TME which is then converted to AMP and subsequently to adenosine by ectonucleotidases (CD39 and CD73). Adenosine binds its receptors (mainly A_2AR and A_2BR) to stimulate intracellular accumulation of cAMP and activation of protein kinase A (PKA), which in turn produces immunosuppression by acting on several downstream targets.

Targeting KCa3.1 for Cancer Therapy

One of the most important immunosuppressive effects of adenosine is a reduction of immune cell infiltration in tumors, by mechanisms that are not completely elucidated. Recently, a paper by Laura Conforti’s group³ has revealed a key molecular player in the suppression of T cell motility mediated by adenosine.

In their article, Chimote et al.³ studied how adenosine influences the chemotaxis of circulating CD8⁺ T cells extracted from head and neck squamous cell carcinoma (HNSCC) patients, and the molecular mechanisms modulating their chemotactic activity. The chemotaxis of T cells from HNSCC patients was more sensitive to the inhibitory effects of adenosine than that of control T cells extracted from healthy patients. This higher sensitivity, of patient-extracted CD8⁺ T cells, to adenosine was unexpectedly not dependent on higher A_2AR signaling, but on post-translational inhibition of the activity of the Ca²⁺ activated K⁺ channel, KCa3.1.

Description: Activator of epithelial KCa channels Chemical Name: 1-Ethyl-2-benzimidazolinone Purity: ≥99% (HPLC)

This channel provides part of the electrochemical driving force for Ca²⁺ influx into the cell, which is necessary for various aspects of CD8⁺ T cell function including proliferation, gene expression, cytokine production and motility. In fact, when the KCa3.1 channel was pharmacologically activated by 1-ethyl-2-benzimidazolinone (1-EBIO), proper chemotaxis was restored in activated CD8⁺ T cells from HNSCC patients. These findings position KCa3.1 as an important regulator of chemotaxis and highlight the potential of KCa3.1 activators as novel pharmacological tools for the treatment of HNSCC and other solid tumors.

Significance

Improving the infiltration of CD8⁺ T lymphocytes into solid tumors could in turn increase significantly the effectiveness of immune cancer therapies. The findings by Chimote et al.³ provide a clear rationale for targeting KCa3.1 activity, a novel T cell chemotaxis regulatory mechanism, towards the improvement of CD8⁺T cell cytotoxicity in HNSCC.

Learn more about hypoxia signaling

Yoskaly Lazo Fernandez, PhD
Emory University, Department of Medicine/Renal Division
Dr. Lazo-Fernandez is interested in understanding the dietary factors that contribute to the development of hypertension and other chronic diseases.

References

1. Vijayan D, Young A, Teng MW, Smyth MJ. Targeting immunosuppressive adenosine in cancer. Nature reviews Cancer. 2017;17(12):765. doi:10.1038/nrc.2017.110.
2. Allard D, Turcotte M, Stagg J. Targeting A2 adenosine receptors in cancer. Immunology and Cell Biology. 2017;95(4):333. doi:10.1038/icb.2017.8.
3. Chimote AA, Balajthy A, Arnold MJ, Newton HS, Hajdu P, Qualtieri J, Wise-Draper T, Conforti L. A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment. Sci Signal. 2018;11(527):eaaq1616. doi:10.1126/scisignal.aaq1616.