Adenosine-producing regulatory B cells in head and neck cancer
S Jeske, Matthias Brand, Andreas Ziebart, Simon Laban, Johannes Doescher, Jens Greve, Edwin K. Jackson, Thomas K. Hoffmann, Cornelia Brunner, Patrick J. Schuler
Abstract
Abstract Background Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (B reg ). Recently, we have shown that B reg suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of B reg in head and neck cancer remains unclear. Methods Blood ( n = 42) and tumor tissue ( n = 39) of head and neck cancer patients and healthy donors ( n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca 2+ influx and ADO production was analyzed in B reg and effector B cells (B eff ) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A 2A was analyzed in a murine head and neck cancer model. Results ADO-producing B reg were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton’s tyrosine kinase (BTK) and Ca 2+ influx only in B eff . The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A 2A significantly reduced tumor mass and increased B cell infiltration, in vivo. Conclusion Our data demonstrate the presence of a novel ADO-producing B reg population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing B reg can influence the function of B eff cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.