Poster Presentation 36th Lorne Cancer Conference 2024

The ribotoxic stress response regulates tumour immune escape via MHC-I transcript decay (#234)

Keziah E Ting 1 2 , Nicola E Caine 1 , Rasan M Sathiqu 1 , Kristin K Brown 1 2 3
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, Australia

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. Most solid tumours exhibit decreased cell surface expression of major histocompatibility complex class I (MHC-I), which hinders the presentation of antigens to tumour-infiltrating T cells and therefore limits anti-tumour immunity. Surprisingly, the metabolic regulation of tumour cell antigen presentation remains poorly understood. In the current project we have investigated the metabolic regulation of MHC-I antigen presentation with a view to identifying 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. Specifically, 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 an adaptive response to ribosome collisions, namely the ribotoxic stress response, which accelerated decay of HLA transcripts encoding MHC-I. Given that nutrient availability is frequently compromised in solid tumours, we believe that ribotoxic stress likely plays a significant role in reducing MHC-I expression to promote immune evasion. Importantly, we have demonstrated that 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.