Project 441367

The immune system protects the body against infectious diseases, as well as inherent diseases such as cancer. The immune system is the first line of defense charged to eliminate cancer cells from the body. However, cancer has evolved mechanisms to evade the immune system, some of which have been exposed and leveraged with powerful immunotherapies. Despite the incredible advances made with new immunotherapies in the past two decades, the majority of cancers remain refractory to immunotherapy through intrinsic and acquired genetic and/or epigenetic mechanisms of resistance. Our understanding of the genes and pathways that program cancer cells to evade the immune system is very limited. In other words, the inventory of secret weapons that cancer cells harbour against the immune system still needs to be fully catalogued. Identifying cancer intrinsic immune invasion genes and the mechanism of action by which these genes help cancer cells evade the immune system will uncover the Achilles heel of cancer and find new ways to weaken cancers against the immune system and immunotherapy. Using state-of-the-art technologies in genetics including systematic genome-wide CRISPR screening, as well as a cutting edge cost-effective single-cell sequencing approach, our lab has identified key genes that help cancer cells evade tumor infiltrating immune cells. One such gene is Adar, which helps cancer cells resist the immune system. It is currently not known how the Adar gene contributes to resistance to immunotherapy; however, preliminary results by our group and others suggest that Adar is involved in innate immunity. The goal of my project is to study how ADAR regulates cancer immune evasion and which molecular pathways synergize with ADAR activity to enhance immunotherapy. In this project, in collaboration with Agios pharmaceuticals company, we also aim to translate our findings to clinical medicine by developing new anti-cancer treatments based on targeting ADAR-mediated pathways.