Project 458812

Pancreatic cancer is the 3rd leading cause of cancer deaths, with less than 10% of patients surviving this cancer. An important reason for this lethality is that pancreatic cancer does not respond well to chemotherapies and immunotherapies. My PhD project focuses on identifying subtypes of pancreatic cancer that may respond to immunotherapies. For treatments like immune checkpoint inhibitors (ICIs) to work, cancers need many immune cells called CD8 T cells within the tumour, a phenomenon known as T cell-inflammation. Specific proteins, called chemokines, are important because they help bring these cells into the cancer. We have evidence that four specific chemokines may be involved in the development of T cell-inflammation in pancreatic cancer. Even though these chemokines may be involved, it is unclear what genetic changes in the cancer, like gene mutations, are responsible for causing this inflammation. Given this, we hypothesize that pancreatic cancers with T cell-inflammation have specific genetic mutations making them more likely to respond to ICIs. To investigate this, first, we will confirm the association of T cell-inflammation with our 4-chemokine score across many different cancer types, focusing on a specific subtype called homologous repair deficient, important for many cancers including pancreatic cancer. Second, we will identify mutations associated with our 4-chemokine score, and correlations with ICI responses. Lastly, we will use mouse models to study the effects of these mutations on T cell-inflammation in pancreatic cancer. We will also use these transplanted mice to study the effects of current treatments combined with immunotherapies, like ICIs. While immunotherapy is currently ineffective in most patients with pancreatic cancer, specific groups of patients may respond. Understanding how T cell-inflammation occurs in pancreatic cancer will help doctors identify which patients should be treated with immunotherapies to improve outcomes.