Abstract 4149: Extensive characterization of the adenosine pathway in human solid tumors gives a hint on cancer indication selection for the A2A receptor antagonist EOS100850

Abstract

Abstract Extracellular adenosine is an immunosuppressive metabolite generated by sequential action of the two ectonucleotidases CD39 and CD73. Tissue hypoxia, which is frequently observed in neopleastic tissues, increases CD39 and CD73 expression, and is a major driver of extracellular adenosine accumulation. High levels of adenosine, predominantly signaling through the A2A receptor (A2AR), dampen innate and adaptive immune cell responses, leading to suppression of antitumor immunity. We therefore developed EOS100850, a potent and highly selective A2A receptor antagonist to treat a wide range of tumor types. With the aim to support selection of cancer indications for EOS100850, we used immunohistochemistry and computer-assisted image analysis to extensively characterize the expression and spatial distribution of markers of the adenosine pathway and the extent of lymphocyte infiltration in ten tumor types. First, 318 primary tumor specimens included in disease-specific tissue microarrays from nine cancer indications were screened for expression of CD39, CD73 and infiltration of A2AR+, CD8+ and Foxp3+ cells. CD39 and CD73 were expressed by immune cells, endothelial cells and other stromal cells as well as by tumor cells, and their expression was increased in hypoxic tumor regions. Expression levels of the two adenosine-generating enzymes were variable among the analyzed cancer types, with lung and gastric tumors displaying the highest levels of expression of CD39 (78% and 95% of samples with high CD39 expression, respectively) and gastric, uterine and lung cancers displaying the highest levels of CD73 (>70% of samples with high CD73 expression). A2AR staining was observed on different immune cell populations, and significantly correlated with CD8+ and Foxp3+ cell densities (p values <0.0001). A2AR+ immune cells were frequently detected in lung, gastric and head and neck tumors (>80% positive samples) but not in kidney and prostate tumors (<20% positive samples). To encompass the inherent heterogeneity of tumor tissues, the expression and spatial distribution of CD39, CD73, A2AR and lymphocyte populations were further analyzed in several lung, colorectal and breast primary tumor resections. These tumor types display high, medium and low levels of the adenosine cloud markers, respectively. CD39 expression as well as densities of A2AR+, CD8+ and Foxp3+ cells were all higher in the tumor surrounding stroma than in the center of the tumor in the three cancer types. Moreover, CD39 and A2AR were significantly correlated with CD8+ and Foxp3+ cell densities in the tumor center but not in the stroma. Altogether these data strongly support the relevance of targeting A2AR and the adenosine pathway in immuno-oncology, and pave the way to the identification of the cancer types that will benefit more from EOS100850. Citation Format: Noemie Wald, Chiara Martinoli, Marjorie Mercier, Annelise Hermant, Florence Nyawouame, Joao Marchante, Charlotte Moulin, Vanesa Bol, Stefano Crosignani, Veronique Bodo. Extensive characterization of the adenosine pathway in human solid tumors gives a hint on cancer indication selection for the A2A receptor antagonist EOS100850 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4149.