LAUSR

High levels of extracellular adenosine, often found in the tumor microenvironment (TME), promote immune suppression mainly through the A2A receptor (A2AR) expressed by tumor-infiltrating immune cells. Inupadenant (formerly known as EOS100850) is an oral, non-brain penetrant, potent and highly selective small molecule antagonist of A2AR. In a Phase I/Ib clinical trial (NCT02740985), inupadenant as monotherapy showed initial evidence of clinical benefit in subjects with advanced solid tumors. In this study, tumor biopsies with a high number of A2AR-expressing immune cells at baseline were associated with response or stable disease.We now report that infiltration of A2AR+ cells was strongly correlated with the expression of B- and, more specifically, antibody-secreting cell (ASC)-related genes, as assessed by gene expression (Nanostring) and immunohistochemistry (IHC), hinting at a potential novel role for A2AR in B cell biology. Therefore, we explored the expression and function of A2AR in human B cells. Immunocytochemistry staining of A2AR on sorted tonsillar B cell subsets showed that A2AR was predominantly expressed on ASCs, including plasma cells and plasma blasts versus naïve or memory B cells. The preferential expression of A2AR by ASCs was confirmed on NSCLC tissues by multiplex immunofluorescence. In addition to A2AR, ASCs expressed other adenosine pathway markers such as CD39, suggesting that the adenosine pathway is a key mechanism through which ASC functions may be modulated. Using B cells derived from peripheral blood, the A2AR agonist CGS-21680 was shown to inhibit the maturation of B cells into plasma cells, and that maturation could be fully restored by inupadenant. CGS-21680 did not affect B cell or plasma cell viability, indicating that the effect of A2AR signaling on plasma cell differentiation is not due to preferential plasma cell death in culture. Importantly, baseline expression of B cell- and ASC-related markers measured by Nanostring and IHC was associated with response or stable disease to inupadenant monotherapy, supporting the notion that these cells may be a novel target of inupadenant. This is in line with recent reports showing that B cells, plasma cells and tertiary lymphoid structures are associated with favorable responses to cancer immunotherapy. Interestingly, four out of the five non-progressors treated with inupadenant as monotherapy and with available biomarker data showed a reduction in ASC infiltration after inupadenant treatment, suggesting that inupadenant may promote terminal plasma cell differentiation and migration out of the tumor tissue and to the bone marrow.Altogether, these data support a novel plasma cell-centric mechanism of action of inupadenant, which may complement its reported T cell-mediated anti-tumor activity. Citation Format: Chiara Martinoli, Paola Tieppo, Marjorie Mercier, Hussein Shehade, Noemie Wald, Anais Vezzu, Annelise Hermant, Boris Pirlot, Stephanie Ma, Maurizio Ceppi, Yvonne McGrath, Maura Rossetti. A novel plasma cell-based mechanism of action of adenosine immunomodulation and A2AR antagonism. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4135.