Enhanced inhibition of chemotaxis by adenosine in peripheral blood CD8+ T cells of head and neck cancer patients

Abstract

Abstract Adenosine (Ado) accumulates in high concentrations in solid tumors where it contributes to the failure of the immune cells to eliminate cancer cells. We have previously shown in healthy T cells that Ado acts via A2A receptors and inhibits T cell motility by suppressing KCa3.1 channel function. Herein, we conducted experiments to elucidate the effect of Ado on the chemotactic abilities of peripheral blood T cells (PBTs) from head and neck squamous cell carcinoma (HNSCC) patients. CD8+ PBTs were isolated from HNSCC patients prior to any form of treatment and healthy donors (HD), and activated with CD3/CD28 antibodies. CD69 expression indicated that comparable activation was achieved in HNSCC and HD T cells. Experiments to measure chemotaxis towards a CXCL12 gradient were performed on T cells suspended in a collagen matrix, which resembles the fibrous network within solid tumors. Chemotaxis was evaluated by determining the center of mass along the Y-axis (Y-COM), which reflects the location of the cells at the end of the experiment and is indicative of their ability to move towards the chemokine gradient. PBTs of HNSCC patients and HDs underwent comparable chemotaxis in the CXCL12 environment. Next, we compared their chemotaxis when Ado was added to the chemokine gradient. Ado was responsible for a significantly greater reduction in the Y-COM in HNSCC (~82%, n=16) compared to HD (~26%, n=7; p=0.012). This effect was mimicked by the A2A receptor agonist CGS21680 and was reversed by the A2A receptor antagonist SCH5826. Our data suggest that Ado acts via A2A receptors and suppresses chemotaxis in HNSCC patients to a greater degree than their healthy equivalents, which may limit their ability to effectively penetrate the tumor.