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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Maria Anisimova, Zurich University of Applied Sciences, Switzerland
- Second opponent: Dr. Jennifer Meadows, Uppsala University, Sweden
- Third member and chair of the evaluation committee: Professor Erik Dissen, University of Oslo
Chair of the Defence
Professor Karl-Johan Malmberg, University of Oslo
Principal Supervisor
Scientific Officer Trevor Clancy, NEC OncoImmunity AS
Summary
The Human Leukocyte Antigen (HLA) region accounts for a relatively small segment of approximately 4 million base pairs in chromosome 6 occupying only 0.13% of the entire human genome, yet this small region has been established to be associated with the greatest number of human diseases such as diabetes, rheumatoid arthritis, psoriasis, asthma, and cancer. Its main function is to enable the body to recognize foreign or “non-self” epitopes and to present them on its surface to T cells, which instigate an immune attack toward infected host cells, or transformed cancer cells. A notable feature of the HLA region consists of its highly polymorphic nature: thousands of different variations of HLA genes (or HLA alleles) can be found in the human population. HLA typing consists of identifying an individual’s combination of HLA alleles. Historically, the most common reason for HLA typing was finding out which individuals were compatible to provide safe tissue transplants that do not undergo immune tissue rejection in the recipient host (graft versus host disease). With the growing development in the immunotherapy field, HLA typing became important for cancer research as some immunotherapies rely on the ability of patients’ HLA molecules to successfully bind and present tumor antigens on the cell surface. Multiple evidence suggests that tumors may downregulate, upregulate, or alter the heterozygosity of HLA as protective property against immune recognition and elimination of cancer cells. Detection of germline HLA genotypes and assessment of heterogeneity in this region may be crucial for the prediction of immunotherapy clinical outcomes. At the same time, somatic alterations in the HLA region may modulate the immune escape mechanisms in tumors as well as regulate the repertoire of immunogenic neoantigens presented to T cells. Thus, knowledge of a specific HLA genotype, its expression, and somatic alterations in this region is crucial for the understanding of the interplay between the tumor and the immune system and the development of effective personalized immunotherapies and should ideally be integrated into clinical practice. Until recently it was not technologically possible to comprehensively profile the HLA region in the cancer context, however, the recent advent of next-generation sequencing (NGS) technology offers an opportunity to finally address this limitation. Despite this technological advancement, there is a lack of bioinformatics software for integrative analysis of both the germline and the tumor HLA region. My research has been focused on both improving the current NGS-based HLA typing strategies and bridging this gap by creating a universal tool for a broad-range analysis of the HLA region in humans, as well as studying the consequences of different types of HLA alterations on tumor development.
This work describes the state-of-the-art bioinformatics algorithms to genotype and characterize the HLA region in healthy and tumor tissues. The developed method is unique in the sense that it can be applied to different types of data, including Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), and RNA sequencing data, detect alleles that differ in coding regions beyond antigen recognition site as well as non-coding regions, recognize novel alleles and somatic mutations in tumors, and infer personalized expression of HLA molecules. The method for HLA genotyping has an overall accuracy of above 99% and allowed to discover a previously uncharacterized allele which has been assigned the name HLA-B*44:02:01:52 and cataloged by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA system. Furthermore, the potential of the algorithm in studying tumor-immune interactions has been demonstrated by applying the method to tumor samples from two different subtypes of breast cancer (triple negative breast cancer and estrogen receptor-positive HER2 negative cancer) and normal adjacent to tumor tissues.
The rapidly growing clinical applications of personalized medicine reveal the importance of ultrahigh-resolution typing and accurate characterization of the HLA complex. This work is of great value for the research in immunology as well as various clinical applications including hematopoietic stem cell and organ transplantations, and the development of personalized cancer vaccines.
Additional information
Contact the research support staff.