Adenosine-producing regulatory B cells in head and neck cancer

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-020-02535-6) contains supplementary material, which is available to authorized users.