dc.contributor.author | Kim, Youra | |
dc.date.accessioned | 2021-08-24T15:07:46Z | |
dc.date.available | 2021-08-24T15:07:46Z | |
dc.date.issued | 2021-08-24T15:07:46Z | |
dc.identifier.uri | http://hdl.handle.net/10222/80720 | |
dc.description.abstract | Cancer immunotherapies (re)educate the body’s natural defenses to recognize and attack malignant cells. The consequent anti-tumor immunity is highly specific, long-lasting, and often dependent on CD8 T cells, the presence of which in the tumor microenvironment correlates with a favorable cancer prognosis. CD8 T cell activity requires T cell receptor-mediated recognition of antigenic peptides (i.e., epitopes) bound to class I major histocompatibility complex (MHC-I). The sequences of the MHC-I-bound peptides can be used to study cognate, antigen-specific T cells or design peptide vaccines to develop immunity against certain epitopes. However, despite recognizing the important role of CD8 T cells in immunotherapies, the identity of the epitopes dictating anti-tumor CD8 T cell responses have remained largely elusive.
This thesis aims to address this knowledge gap by elucidating the MHC-I-restricted epitopes in the context of an oncolytic virus (OV)-based cancer immunotherapy. In addition to their direct tumor-destructive effects, OVs activate anti-tumor CD8 T cells and overturn tumor-associated immune evasion mechanisms. OV-mediated increase in tumor MHC-I expression is of particular relevance to this thesis and lays the foundation for our pursuit of discovering therapy-modulated MHC-I-bound peptides that direct anti-tumor immunity.
In this work, the latest advances in mass spectrometry were utilized to investigate the array of tumor MHC-I-bound peptides (i.e., MHC-I peptidome) following oncolytic reovirus treatment, either as a monotherapy or as a combination therapy with immune checkpoint blockade. Within the therapy-modulated MHC-I peptidome, immunogenic epitopes were identified and administered as peptide vaccines to enhance OV efficacy. Furthermore, an immunoinformatics approach was used to discover MHC-I-restricted epitopes of reovirus and the corresponding anti-viral CD8 T cells were characterized. These viral epitopes were then used to antigenically reprogram the tumor MHC-I peptidome, resulting in viral peptide-presenting cancer cells as targets of anti-viral CD8 T cells, for the repurposing of anti-viral immunity. Overall, the elucidation of the MHC-I-restricted epitopes of tumors and reovirus provided an insight on the anti-tumor and anti-viral CD8 T cell responses during reovirus administration, and yielded information that can be exploited to further potentiate CD8 T cell immunity of OV therapy. | en_US |
dc.language.iso | en | en_US |
dc.subject | Oncolytic virus | en_US |
dc.subject | Cancer immunotherapy | en_US |
dc.subject | Class I major histocompatibility complex | en_US |
dc.subject | MHC peptidome | en_US |
dc.subject | Epitope mapping | en_US |
dc.title | Class I Major Histocompatibility Complex Restricted Epitopes in Oncolytic Virus Infection and Therapy | en_US |
dc.type | Thesis | en_US |
dc.date.defence | 2021-08-16 | |
dc.contributor.department | Department of Pathology | en_US |
dc.contributor.degree | Doctor of Philosophy | en_US |
dc.contributor.external-examiner | Dr. Lee-Hwa Tai | en_US |
dc.contributor.graduate-coordinator | Dr. Paola Marcato | en_US |
dc.contributor.thesis-reader | Dr. David Waisman | en_US |
dc.contributor.thesis-reader | Dr. Paola Marcato | en_US |
dc.contributor.thesis-reader | Dr. Jun Wang | en_US |
dc.contributor.thesis-supervisor | Dr. Shashi Gujar | en_US |
dc.contributor.ethics-approval | Received | en_US |
dc.contributor.manuscripts | Yes | en_US |
dc.contributor.copyright-release | Yes | en_US |