The role of VISTA expression by tumour macrophages in limiting the efficacy of chemotherapy and checkpoint inhibitors

Women with triple negative breast cancer (TNBC) have limited treatment options and often rely heavily on chemotherapy. Unfortunately, many fail to show a complete response to this and suffer recurrence at the primary or distant sites within 1-3 years. This means that there is an urgent need to develop new ways to prevent this.

We recently identified a subset of CD206+ macrophages in chemotherapy-treated breast tumours that gather around blood vessels and drive relapse. Our latest data show that these cells are immunosuppressive and upregulate a protein called VISTA. This is a potent, broad-spectrum negative checkpoint regulator (NCR) that inhibits the anti-tumour functions of cytotoxic T cells (CTLs) in tumours. We believe that macrophages expressing high levels of VISTA in the perivascular niche of tumours after chemotherapy inhibit CTLs upon their entry into tumours, helping to protect cancer cells from destruction by the immune system, and facilitating tumour regrowth.

The PhD student will conduct experiments to see whether CD206-targeted liposomes containing an inhibitor for VISTA stimulates tumour CTLs after chemotherapy, augments anti-tumour immunity, and prevents subsequent relapse. The project will also investigate with these liposomes can augment the efficacy of checkpoint inhibitors like anti-PD1 and anti-PDL1. These new combination treatment treatments will be tested in various experimental models of TNBC and, if successful, will then progress into early-phase clinical trials for TNBC patients.