A role for the cell guidance receptor EphA3 in the immune tumour microenvironment. Mary E. Vail1,2, Rae H. Farnsworth2*, Stacey Allen1, Andrew M. Scott1,3 and Peter W. Janes1,2,3 1Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084 2Monash Biomedical Discovery Institute, Monash University, Clayton, VIC, 3800 3School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086. *Present address: Peter MacCallum Cancer Centre, Grattan St, Melbourne VIC 3000 Tumour progression relies on interactions between tumour and host–derived stromal and myeloid cells within the 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 over 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 bone marrow-derived mesenchymal stromal cells (MSCs), as well as on myeloid cell types, which together support tumour growth via promoting vasculogenesis and immune evasion . Treatment of mice bearing prostate and colon cancer xenografts with the anti-EphA3 monoclonal antibody IIIA4 inhibited tumour growth, associated with disruption of the TME. To further investigate the role of EphA3 in the TME we developed mice with inducible shRNA-mediated knock-down of endogenous EphA3 expression. We confirmed robust reduction of EphA3 in stromal and myeloid cells recruited to the TME in syngeneic mouse tumour models. Reduced EphA3-expression correlated with decreased tumour vascularity and growth. Also, in the myeloid-dependent MC38 colon cancer model, EphA3 knock-down reduced recruitment of myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs). Consistent with immune modulation, reduced myeloid content was accompanied by increased T cell infiltration and increased sensitivity to immune-checkpoint inhibition. Our results thus suggest EphA3 is a novel target in the inflammatory TME, with potential therapeutic utility. 1. Vail, M.E., et al., Targeting EphA3 Inhibits Cancer Growth by Disrupting the Tumor Stromal Microenvironment. Cancer Research, 2014. 74(16): p. 4470-4481.
Olivia Newton-John Cancer Research Institute
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