Proteomic and immunopeptidomic characterisation of head and neck cancers
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Embargo End Date
ICR Authors
Authors
Melake, JM
Document Type
Thesis or Dissertation
Date
2024-09-13
Date Accepted
Abstract
Head and neck squamous cell carcinoma (HNSCC) exhibits distinct clinical
characteristics that can be associated with the initiation factors of carcinogens or HPV
infection, the latter being associated with better survival outcomes following
chemotherapy and radiation. Understanding the underlying molecular differences,
particularly with regards to tumour recognition by the immune system, is crucial for
advancing treatment options. Our study employs quantitative proteomics in HNSCC cell
lines and identifies a HPV protein signature linked to TRIM28 chromatin regulation rather
than solely HPV oncoprotein-driven protein deregulation. We further describe four cancer
testis antigens (CTA) associated with HPV+ diseases. By treating cell lines with radiation
and chemotherapy, we outline treatment response signatures unique to HPV+ and HPVcells
and identify promising radiation-induced protein targets in HPV- cells with potential
for combined targeted therapies. We implement a quantitative immunopeptidome
workflow, and use it to characterise the HLA antigen landscape of HNSCC cell lines,
finding no HPV-dependent differences in immunopeptidome size or functional
enrichment of peptide source proteins. However, we discover tumour-associated,
recurrent candidate peptides and CTA peptides from the SPAG and MAGE protein
families highly recurrent in both HNSCC cell lines and patients. Radiation-driven
modulation of cell line immunopeptidomes reveals a larger subset of upregulated
peptides compared to downregulated ones, which are predominantly presented on HLAB.
These radiation-induced peptides partially originate from stress-related proteins,
linking protein-level to immunopeptidome-level modulation. Additionally, we investigate
immunopeptide trajectories during radiotherapy in HNSCC patient blood plasma,
mapping temporal peptide abundance changes in a pilot study of six patients. We
discover recurrent radiation-induced peptides considered as prognostic biomarkers in
various cancers and linked to poor disease outcomes. Overall, our study provides novel
insights into protein and immunopeptidome regulation in HNSCC at baseline and posttreatment,
uncovering tumour-associated, radiation-induced, or CTA protein and peptide
targets that could ameliorate HNSCC treatment strategies.
Declaration
I confirm that:
• the work present in this thesis is my own and where information has been derived from other
sources, I confirm that this has been indicated in the thesis;
• that the thesis does not exceed the prescribed word limit; and
• that I will keep my contact details updated with the Library Theses Office and Registry
throughout the examination process.
Signature: Date:
Citation
2024
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Functional Proteomics