ADGRL4/ELTD1 expression in breast cancer cells induces vascular normalisation and immune suppression.
Sheldon H., Bridges E., Silva I., Masiero M., Favara DM., Wang D., Leek R., Snell C., Roxanis I., Kreuzer M., Gileadi U., Buffa FM., Banham A., Harris AL.
ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumour types and this correlates with a good prognosis. Expression has also been reported in some tumour cells with high expression correlating with a good prognosis in hepatocellular carcinoma and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumours stain positively for ELTD1, with 9% having high expression that correlates with improved relapse free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumours expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumours had larger and better perfused vessels and tumour-endothelial cell interaction led to the release of pro-angiogenic and immune modulating factors. M2-like macrophages increased in the stroma along with expression of PD-L1 on tumour and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1 regulated tumour growth in the presence of an NY-ESO-1 specific immune response. Eltd1 positive tumours also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumours. ELTD1 may be useful as a selection marker for such therapies. Implications: ELTD1 expression in breast tumour xenografts creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.