Author Identifier
Luisa Marie Pinnel: http://orcid.org/0009-0003-7025-8736
Date of Award
2026
Keywords
TCR repertoire, HLA genotype, melanoma, checkpoint blockade immunotherapy, ICI, Liquid biopsy, response biomarker, blood biomarkerä
Document Type
Thesis - ECU Access Only
Publisher
Edith Cowan University
Degree Name
Master of Medical and Health Science by Research
School
School of Medical and Health Sciences
First Supervisor
Aaron Beasley
Second Supervisor
Elin Gray
Abstract
Incidence rates for melanoma have increased in recent years and while immune checkpoint inhibitors (ICIs) have revolutionised melanoma treatment and prolonged survival rates, half of stage IV melanoma patients still do not show long-term response rates to treatment. Currently, there are no blood-based biomarkers that can predict ICI therapy response and thereby guide treatment selection used in the clinic. Human Leucocyte Antigen (HLA) genotyping and peripheral T-Cell Receptor (TCR) repertoire have previously been shown to be predictive for treatment outcome and increased survival rates in melanoma and other cancers. The prime reason for investigating HLA and TCR stems from the basic principle of immune activation, in which HLA molecules present for instance cancer antigens that bind to TCRs on T-cells and thereby cause clonal selection and expansion of activated T-cells to create an effective immune response against cancer. Therefore, we hypothesised that HLA genotyping and TCR repertoire profiling can serve as biomarkers to associate ICI response in metastatic melanoma.
A total of 305 late-stage melanoma patients were recruited for discovery and validation cohorts for HLA genotyping and TCR-β CDR3 sequencing, where possible. We analysed HLA genotyping features, such as zygosity at HLA Class I and II, supertypes, and evolutionary divergence. Secondly, TCR repertoire features, such as number of unique clones, measurement of the similarity of clone sizes (evenness), Shannon diversity, and convergence of clones were calculated. All features were primarily compared against clinical benefit (CB), progression free survival (PFS) and overall survival (OS) outcomes.
Results failed to demonstrate that HLA genotype and TCR repertoire features could serve as potential biomarkers for ICI response. The discovery cohorts highlighted some significant findings, such as high evolutionary divergence levels in HLA gene locus B providing better PFS outcomes and presence of supertype HLA-B27 significantly worsening PFS and OS. Moreover, TCR repertoire features seemed to show valuable insights with increased richness and diversity levels significantly impacting longer OS and PFS outcomes, as well as CB in patients in the discovery phase. However, these results could not be validated in an independent cohort. Therefore, a joined analysis of both HLA and TCR using the same discovery and validation cohorts failed to distinguish promising associations as response biomarkers.
Overall, while no conclusive associations between HLA genotyping, TCR repertoire features and response to ICI therapy was identified in this dataset, cohort limitations could have played a major role in biasing our analyses and thereby limiting statistical power, which is why further research in this area with large, consolidated cohorts is warranted.
Access Note
Access to this thesis is embargoed until 13th May 2031
Recommended Citation
Pinnel, L. M. (2026). TCR repertoire and HLA genotype as response biomarkers to checkpoint blockade immunotherapy in advanced melanoma patients. Edith Cowan University. https://doi.org/10.25958/dv4n-nd75