Ng, Kien Hoe; (2022) Mapping the MHC-I Immunopeptidome in Solid Tumours: The Impact of Cellular Stress on Antigen Presentation. Doctoral thesis (Ph.D), UCL (University College London).

Text PhD Thesis [K H Ng] Final - May 2022.pdf - Accepted Version Access restricted to UCL open access staff until 1 June 2025. Download (6MB)

Abstract

Cellular stress is a hallmark of carcinogenesis. Cancer cells may undergo stress due to inherent factors, such as genotoxic or metabolic abnormalities, or extrinsic stressors such as cytotoxic chemotherapy. My hypothesis is that cellular stress can modulate the crosstalk between immune and tumour cells, by impacting the antigen processing pathway and resulting immunosurveillance. By applying machine-learning on data derived from a Phase 2 clinical trial in Head and Neck Cancer, our team generated a multiparameter predictive signature to systemic therapy. I demonstrated that the signature consisted predominantly of immunological parameters, suggesting that the extrinsic stress imposed by platinum-based chemotherapy on the tumour may manifest by changes in the anti-tumoural immune response. I subsequently explored the impact of cytotoxic chemotherapy in a variety of cell lines, with a focus on the unfolded protein response. I demonstrated that cisplatin chemotherapy causes upregulation of IRE1 in head and neck and lung cancer cell lines. Using knockout models, I demonstrated that abrogation of the IRE1 signalling pathway increases HLA expression and number of peptide sequences presented in head and neck cell lines. This was accompanied by an upregulation in proteasomal activity. To study the effect of intrinsic cellular stress on antigen presentation, I performed direct HLA-I ligand elution from 19 tissue samples derived from 11 patients with head and neck cancer, and compared the immunopeptidome repertoire between matched tumour and benign adjacent tissue (n=8) The output covered at least 29 HLA-I allotypes presenting 11,485 and 5,110 peptides in tumour and normal adjacent tissue respectively. I observed that interindividual variability of the immunopeptidome repertoire outweighs inter-tissue heterogeneity, highlighting the dependence of peptide presentation on HLA polymorphism. I identified a distinct set of peptides which were present exclusively on tumour tissue of patients with the commonly occurring allele (HLA*03:01) and sequence motif, which warrant investigation as candidates for cancer vaccines.

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