Natural Killer cells for precision therapy in non-small cell lung carcinoma: a focus on KRAS/TP53 comutated tumours.

Lung cancer is the most common cause of cancer death worldwide and Nova Scotia demonstrates the highest incidence rate of all Canadian provinces. Most lung cancer patients have a subtype that falls under the category of non-small cell lung carcinoma (NSCLC). This group of lung cancers is known for its genetic instability meaning, it is not uncommon for a single patient's tumour to have multiple genetic mutations. Interestingly, the rate of mutation in the Kristen rat sarcoma (KRAS) gene that promotes tumour growth is higher in the Nova Scotian population than the global average. Additionally, >40% of NSCLC patients with a KRAS mutation possess a second commutation in the tumour protein 53 (TP53) gene which may be useful for treatment. Immunotherapy uses our body's own immune system to help fight the cancer, rather than toxic chemicals. For NSCLC, these immunotherapies mainly work through activation of an immune cell type called Natural Killer (NK) cells. Reflected in their name, these cells are uniquely designed to kill stressed and dying cells and have shown impressive success for cancer control. My project will address how KRAS and TP53 comutations affect survival outcomes and the function of NK cells in NSCLC. To do this, I will use a combination of international and local genetic databases to analyze NSCLC patient data for KRAS and TP53 comutations. This information will be used to determine the relative impact of each mutation on survival. I will then use locally available NSCLC tissue samples for staining that will identify the number of tumour-infiltrating NK cells. This data will be correlated with clinical characteristics such as response to therapy and survival outcomes. Finally, I will use NK cells from healthy donors and challenge them with NSCLC cells possessing the relevant mutations for detailed analysis. Together, these experiments will illustrate how KRAS/TP53 comutations affect NK cell control of NSCLC with implications for future therapies.