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

Paola Tieppo¹Hussein Shehade¹Chiara Martinoli¹Marjorie Mercier¹David Carbonez¹Nicolas Rosewick¹Sophie Jung¹Anais Vezzu¹Boris Pirlot¹Noemie Wald¹Stephanie Ma¹Lucas Chaible¹Reece Marillier¹Francesco Strozzi¹Marie-Caroline Dieu-Nosjean^2,3,4Joao Marchante¹Margreet Brouwer¹Erica Houthuys¹Michael Deligny¹Yvonne McGrath¹Maura Rossetti^1*

• ¹iTeos Belgium SA, Gosselies, Belgium
• ²Sorbonne Universite, Paris, France
• ³INSERM, Paris, France
• ⁴Centre d'Immunologie et de Maladies Infectieuses, Paris, France

High levels of extracellular adenosine, highly abundant in the tumor microenvironment, promote immune suppression mainly through the A2AR expressed by tumor-infiltrating immune cells. Here we show that the frequency of plasma cells is 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, plasma cells and plasma blasts (PCs and PBs, respectively, and collectively referred to as antibody-secreting cells (ASCs), express high levels of A2AR. Given the importance of tumor-infiltrating B and PCs in antitumor responses, we investigated how adenosine impairs their numbers and function. Triggering of A2AR inhibited B cell maturation into ASCs and immunoglobulin production in vitro, and impaired upregulation of PC genes upon stimulation. These effects were restored by inupadenant (EOS100850), a potent and highly selective small molecule A2AR antagonist. Spatial transcriptomics analysis of tumor biopsies from patients treated with inupadenant revealed that ASCs specifically increased in tertiary lymphoid structures. 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.