Breast Cancer Metastasis Research Group

Defining the Glycoprotein-NMB (GPNMB) Domains Required for T Cell Suppression and Immunosuppressive Microenvironment Formation in TNBC 

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype, associated with high rates of metastasis and a lack of effective targeted therapies. TNBC is the most immunogenic breast cancer subtype, characterized by prominent immune cell infiltration, notably CD8+ T cells. CD8+ T cells play a central role in mediating anti-tumour responses through the release of cytotoxic molecules, including perforin and granzyme B. However, a number of tumour-intrinsic mechanisms can suppress CD8+ T cell effector functions, dampening the antitumour immune response. Glycoprotein-NMB (GPNMB) is overexpressed in various cancers, including melanoma and TNBC, promotes metastasis, and correlates with poor prognosis in patients. The pro-tumorigenic and pro-metastatic effects of GPNMB are mediated through tumour-intrinsic factors that promote cancer cell migration and invasion, in addition to mechanisms that induce a vascularized and immunosuppressive tumour microenvironment (TME). However, the mechanism by which GPNMB suppresses CD8+ T cell responses remains unknown, in part because the domain(s) through which GPNMB interacts with CD8+ T cells to induce immunosuppression have yet to be identified. The goal of my project is to determine which domain(s) of GPNMB are important in mediating this interaction with CD8+ T cells by generating GPNMB mutants in a mouse mammary cancer cell line and (1) assessing their impacts on tumour growth in vivo and their ability to induce an immunosuppressive tumour microenvironment and (2) assessing the ability of the GPNMB mutants to suppress T cell activation in vitro.