Grant: Doctoral Research Award: Canada Graduate Scholarships

Cancer is the leading cause of death in Canada, but recent advances in new treatments such as immunotherapy have improved treatment outcomes. Immunotherapies use the immune system, namely a type of cell called cytotoxic T lymphocytes (CTL), to kill tumour cells. While many cancers respond to immunotherapy, non-immunogenic ("cold") tumours are generally nonresponsive. The study of these cold tumours showed that many cold tumours do not properly express major histocompatibility complex class I (MHC-I) proteins. CTLs need MHC-I to detect and kill tumour cells. Therefore, MHC-I downregulation decreases CTL activity. Currently, there are no effective ways of restoring MHC-I expression in cold tumours. My goal is to engineer a vaccinia virus (VACV) to express MHC-I after infection and study MHC-I restoration and CTL activity in cold tumours treated with the virus. I inserted a single-chain dimer (SCD) construct made up of MHC-I and its cofactor, beta2-microgobulin, into a safe and cancer selective VACV backbone by genetic recombination to create VACV-SCD. I will investigate virus growth and cell killing in a variety of mouse cell lines known to be unresponsive to immunotherapies. I will also confirm the expression and function of MHC-I in infected cells. The safety and effectiveness of VACV-SCD will then be tested in mice with cold tumours. After implanting tumours in mice and injecting the tumours with VACV-SCD, the mice will be monitored for tumour growth and survival. Tumours will also be dissected to quantify CTL populations and perform single-cell RNA sequencing. Single-cell RNA sequencing will provide a complete picture of the cell types present in the tumour after VACV-SCD treatment. Together, these results will make up a comprehensive evaluation of VACV-SCD efficacy in making cold tumours more immunogenic. This will reveal whether VACV-SCD treatment can be used in cold tumours to increase clinical success rates of cancer immunotherapy.