Cancer cells are often exposed to harsh metabolic conditions where fluctuations in nutrient availability occur. Restricted availability of some nutrients (e.g. amino acids) and overabundance of others (e.g. lactate) contributes to the reprogramming of cellular metabolism, which is a recognised hallmark of cancer. Furthermore, the process of cellular transformation and tumorigenesis creates new metabolic demands that have profound impacts on a variety of cell types that occupy the tumour microenvironment (TME). T cells, for example, are often compromised within the TME due to competition for nutrients, resulting in impaired T cell function and anti-tumour activity. In addition, tumour cells often disrupt antigen presentation to further suppress and hinder T cell function. However, the metabolic regulation of tumour cell antigen presentation remains poorly understood.
Using a cell culture model with enhanced physiological relevance, we have investigated the consequences of altered nutrient availability on MHC-I antigen presentation by cancer cells.We have shown that amino acid withdrawal rapidly reduces basal and interferon-gamma-induced cell surface MHC-I, across a diverse range of cancer cell types. Mechanistically, the impact of nutrient availability on MHC-I expression was found to be dependent on an RNA-binding E3 ubiquitin ligase, known as MEX3C. MEX3C was found to mediate the CNOT8-dependent deadenylation and degradation of HLA transcripts encoding MHC-I. Given that nutrient availability is frequently compromised in solid tumours, we believe that the MEX3C-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.