Major histocompatibility complex-1 (MHC-1) antigen presentation is required for T cell activation and cancer cell recognition. Triple negative breast cancer (TNBC) is a highly invasive breast cancer subtype whereby immunogenicity, as reflected by tumour-infiltrating T cells, is strongly associated with patient outcome. I have found that RASAL2-overexpressing cells have low MHC-1-related genes, suggesting an unexplored link between the RAS- GAP and MHC-1/TAP1/IFNGR1 axis. Given that MHC-1 expression is vital for CD8+ T cell activation and cytolytic ability, I hypothesise that RASAL2 downregulates MHC-1 in TNBC to suppress CD8+ T cell activity. This project will investigate the molecular mechanisms of RASAL2/MHC-1/TAP1/IFNGR1 axis regulation and assess the effect of this downregulation on cytotoxic CD8+ T cell effector function. Mass-spectrometry will be used to perform unbiased mapping of RASAL2-protein binding partners that are potentially associated with the immunosuppressive phenotype. Top hits will be validated with co- immunoprecipitation and gain/loss-of-function experiments to assess modulation of the axis. To investigate CD8+ T cell effector function, a TNBC-T cell co- culture system will be established in vitro and validated with 3D spheroids and patient-derived organoids. Furthermore, an immunocompetent TNBC syngeneic mouse model will be utilised to confirm this phenotype in vivo.