Grant: CIHR Fellowship

The human immune system is essential for our body to fight infections and cancer. However, some infectious pathogens and cancer cells can evade the immune system by manipulating their genetic make-up and surroundings. The process of enhancing our immune cells, such as T cells, to enable their potential to fight infections and cancer is called immunotherapy. T cell-based Immunotherapy is currently the most promising approach in our fight against cancer. Although encouraging, immunotherapy has some drawbacks, including high treatment cost and variance of efficacy across patients. Production of off-the-shelf immunotherapies containing long-lived T-cells capable of expanding upon reexposure to cancer cells will help to address the current challenges. Induced pluripotent stem cells (iPSCs) offer an excellent option for developing off-the-shelf T cell immunotherapies. However, the generation of T cells from iPSCs, although achievable, it does not fully recapitulate the key requirements needed for T cell effector function. Here, I aim to interrogate iPSC to T-cell differentiation to produce effective iPSC-derived T-cell populations capable of prolonged and effective anti-cancer function. To do this, I will first perform a lineage-tracing experiment to track the emergence of T-lineage cells from HSCs, and then determine gene expression and chromatin accessibility profiles at a single-cell resolution. Next, I will utilize these data to genetically manipulate the identified regulatory regions to determine the importance of unique areas in determining T-lineage fate and functionality. Transiently targeting these regions, individually or in synergy, will enable the development of novel off-the-shelf iPSC-mediated immunotherapies.