Uncontrolled cell proliferation during tumor progression relies on the interaction between tumour and host–derived stromal and myeloid cells in the vascularised growth-supporting tumor microenvironment (TME). Amongst the proteins instrumental in establishing the TME, Ephs and their cell-associated ephrin ligands are implicated in neoangiogenesis, tissue patterning and invasive tumor growth. Due to their critical, mostly kinase-independent functions in tumor progression, Eph receptors are considered promising anti-cancer drug targets. Amongst these, EphA3 is overexpressed on solid and haematopoietic tumor cells and implicated in maintaining tumor-initiating cells in glioblastoma and leukemia and our anti-EphA3 antibody is the first Eph-targeted therapeutic currently completing Phase-I trials in leukemia.
Somatic mutation profiles of solid cancer genomes suggested kinase-active EphA3 as a tumor suppressor in, but its actual role in solid tumorigenesis remained undefined. We now report the unexpected EphA3 overexpression within the tumor microenvironment of a range of human cancers and tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3+/CD90+/Sca1+ mesenchymal/ stromal cells leads to cell contraction, cell-cell segregation and apoptosis. Treatment of mice with our agonistic α-EphA3 antibody inhibits tumor growth by disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anti-cancer therapy.