Tumour progression relies on interactions between tumour and host–derived stromal and myeloid cells within the stromal tumour microenvironment (TME). Amongst the proteins involved in shaping the TME, Eph receptors and their cell-bound ephrin ligands control cell-cell interactions supporting neo-angiogenesis, invasion and cancer stem cell maintenance, and are increasingly recognised as drug targets. EphA3 is abnormally expressed in a range of solid tumour types, most commonly in cells recruited from the host bone marrow to the tumour. We previously showed EphA3 is expressed on mesenchymal stromal cells (MSCs), which form the tumour stroma and vasculature and support tumour growth. Treatment of mice bearing prostate and colon cancer xenografts with the anti-EphA3 monoclonal antibody mAbIIIA4 inhibits tumour growth, associated with disruption of the TME.
We now report expression of EphA3 on bone-marrow derived myeloid cell types recruited to the tumour, including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which contribute to tumour development and evasion of anti-tumour immune response. To further investigate the role of EphA3 in the TME we developed mice with inducible shRNA-mediated knock-down of endogenous EphA3 expression. We confirm robust reduction of EphA3 in the TME in syngeneic mouse tumour models, notably in myeloid cells in myeloid-dependent MC38 colon cancer allografts. Knock-down or antibody targeting of EphA3 resulted in decreased myeloid cell recruitment and increased T cell infiltration in tumours, and inhibition of tumour growth. Our results thus suggest EphA3 plays multiple tumour-promoting roles in distinct cell populations in the TME.