Targeting the RON-MSP axis and harnessing antitumour γδ T cells to counteract breast cancer metastasis

Breast cancer metastasis accounts for 90% of breast cancer-related deaths. Triplenegative breast cancer (TNBC) is the most aggressive breast cancer subtype and associated with the poorest prognosis, limited treatment options and high relapse rates. Therefore, exploiting new targets to abrogate metastasis are required. We show that mammary tumours from K14Cre;Brca1F/F;Trp53F/F (KB1P) mice, a mouse of model TBNC, have elevated expression of macrophage-stimulation protein (MSP), the ligand of the tyrosine kinase receptor Recepteur d’orginine nantais (RON). Using cell lines derived from KB1P mammary tumours, we observed that endogenous MSP promotes invasiveness in vitro, which can be pharmacologically abrogated by a RON inhibitor. The role of the cancer cell-initiated γδ T cell - IL-17 - neutrophil axis in breast cancer metastasis has been demonstrated in a mouse model of lobular breast cancer. We observed that this metastatic cascade is also relevant in KB1P mice. In contrast to their IL-17 producing counterparts, IFNγ γδ T cells are implied to have anti-tumourigenic potential, but their role in breast cancer metastasis remains elusive. We found that expression of the Vγ1 variant of the T-cell receptor (TCR) is specific to IFNγ γδ T cells. Successful depletion of these cells with an anti- Vγ1antibody was accompanied with a reduction of IFNγ expression on CD3+ T cells. Our long-term goal is to combine γδ T cell immunotherapy with other targeted anticancer therapies. Here, we describe the RON-MSP as viable target for breast cancer treatment and provide initial evidence for a protective anti-tumourigenic role of IFNγ γδ T cells in breast cancer metastasis by priming CD8+ T cells to exert their cytotoxic function