The variety of cell types co-existing within the tumour microenvironment are often exposed to harsh metabolic conditions characterized by fluctuations in metabolite availability. Limited availability of some metabolites (e.g. amino acids) or accumulation of others (e.g. lactate) has been shown to impair T cell function and anti-tumour activity. However, suboptimal T cell function is not the sole cause of impaired anti-tumour immunity. Indeed, cell surface expression of major histocompatibility complex class I (MHC-I), which presents antigens to CD8+ T cells, is downregulated in most solid tumours to suppress and hinder T cell function. Surprisingly, the metabolic regulation of tumour cell antigen presentation remains poorly understood.
My research project has been designed to investigate the metabolic regulation of MHC-I antigen presentation with a view to identify metabolic pathways that can be targeted to enhance anti-tumour immunity. Using a cell culture model with enhanced physiological relevance, we have investigated the consequences of altered nutrient availability on MHC-I antigen presentation by tumour cells.
We have shown that amino acid withdrawal rapidly reduces MHC-I transcript, protein, and cell surface expression across a diverse range of cancer cell types. Mechanistically, the impact of nutrient availability on MHC-I expression was found to be dependent on alternative polyadenylation (APA) of HLA transcripts encoding MHC-I. Amino acid deprivation accelerated transcript decay through preferential usage of distal polyadenylation sites. Given that nutrient availability is frequently compromised in solid tumours, we believe that the APA-dependent regulation of MHC-I likely plays a significant role in reducing MHC-I expression to promote immune evasion. Importantly, loss of cell surface MHC-I expression in the context of amino acid deprivation is reversible and therefore targeting amino acid metabolism affords opportunities to restore MHC-I expression and immune clearance.