Metastatic melanoma is the most lethal form of skin cancer with patients having a 70% higher chance of dying compared to patients diagnosed with other skin cancers (e.g. basal cell carcinoma). Despite significant improvements to treat and manage metastatic melanoma, it remains largely fatal, thus identifying new targets is clinically relevant.
We recently identified an intracellular transport protein, de-identified as TX5, to be upregulated in melanoma cells and to control many biological processes. We have identified that high levels of TX5 predicts poor prognosis for patients with melanoma and is also associated with reduced response to immune checkpoint blockade. In vitro data suggest that TX5 plays an integral role in the transport of various proteins from the cytoplasm to the cell surface which then facilitates cancer cell migration, the release of exosomes, the release of cytokines and the development of tumour vasculature. More specifically, TX5 regulates cell surface expression of adhesion proteins (e.g. integrins and desmoglein-2), the release of cytokines and chemokines (e.g. IL-8 and MCP-1) and regulates vasculogenic mimicry by melanoma cells.
In two syngeneic melanoma mouse models (e.g. B16-F10 and HCmel12), TX5-knockout melanoma cells exhibit a significant reduction in tumour burden compared to the control mice. TX5-KO tumours were significantly smaller and the tumour microenvironment was significantly altered with reduced tumour vasculature, analysis by CyTOF suggests reduced tumour infiltrating pro-cancerous myeloid cells and increased infiltration of anti-cancerous cytotoxic CD8+ T cells. Serum from mice harbouring TX5-KO melanoma cells contained lower levels of pro-inflammatory cytokines and chemokines; further suggesting that TX5 has a modulatory effect on the tumour microenvironment in melanoma.
Finally, and most exciting, is building data that while TX5 is broadly expressed across various cell types, targeting TX5 in healthy endothelial cells does not alter their phenotype or function (i.e. there was no change in adhesion molecule trafficking to the cell surface, cytokine release or blood vessel formation).
Taken together, successful outcomes here may lead to new therapeutic opportunities for patients with metastatic melanoma, particularly for patients who are unlikely to respond to immune checkpoint blockade.