Class I Major Histocompatibility Complex Restricted Epitopes in Oncolytic Virus Infection and Therapy

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.