Project 466648

Lung cancer is the leading cause of cancer death in Canada. While there have been advances in therapies to treat lung cancer, high rates of drug resistance and tumour recurrence emphasize the need for new therapeutic strategies. Tumours often acquire mechanisms to avoid detection by the immune system, allowing them to grow and metastasize. Immunotherapy is a type of treatment designed to overcome these mechanisms and re-activate the bodys immune system to attack tumors. Studies have shown that lung cancers upregulate CD47, a cell surface protein that is a marker of ;self on blood and other cells in the body. Normally, CD47 functions to prevent unwanted immune-mediated killing of healthy cells. By expressing CD47, lung cancer cells use this ;dont eat me signal to block their destruction and clearance by specialized immune cells called antigen-presenting cells (APCs). CD47 inhibitors are a subclass of immunotherapies that can disrupt the interaction between CD47 on cancer cells and its receptor on APCs to promote tumour killing. Our research aims to determine how lung tumour response to CD47 inhibitors is controlled to understand how to use them most effectively in the clinic. We hypothesize that specific genes in lung cancer cells regulate tumour sensitivity to CD47 inhibition. Using CRISPR/Cas9 technology, we will conduct genetic screens to investigate 500 genes whose inactivation is hypothesized to enhance killing of lung tumours by CD47 inhibitors. The findings from this project will reveal genes that can be targeted in combination with CD47 inhibitors to increase therapeutic efficacy. Collectively, our work will inform the development and clinical translation of this new type of immunotherapy to improve lung cancer survival rates in Canada and worldwide.