Inhibition of A2AR alleviates adenosine-mediated suppression of plasma cell differentiation.

Introduction: High levels of extracellular adenosine, highly abundant in the tumor microenvironment, promote immune suppression mainly through the A2AR expressed by tumor-infiltrating immune cells. Given the importance of tumor-infiltrating B and plasma cells (PCs) in antitumor responses, we investigated the effect of A2AR on human B cells. Methods: We performed quantitative mass spectrometry imaging followed by GeoMx analysis on 10 tumor samples. Immunohistochemistry, multiplex immunofluorescence and scRNA-seq were used to assess A2AR expression on tumor and tonsillar B cells. Results: The frequency of PCs was the most negatively affected by adenosine among the immune cells present in the tumor microenvironment. Furthermore, both tonsillar and tumor-associated B cells, including germinal center (GC)-like B cells, PCs and plasma blasts, collectively referred to as antibody-secreting cells (ASCs), expressed high levels of A2AR. Triggering of A2AR inhibited B cell maturation into ASCs and immunoglobulin production Discussion: Altogether, these data demonstrate that A2AR plays a key role in adenosine-mediated inhibition of B cell maturation toward ASCs through a B cell-intrinsic mechanism, and that this effect is fully reverted by inupadenant.