Kathleen Zhang

Snacking on Cancer: Exploring how Cancer Cells Evade Death by Macrophage "Nibbling"

Each time macrophages encounter targets, they make a decision whether to ”engulf,” also known as phagocytose, or “nibble,” termed trogocytosis. Macrophages can be engineered to target cancer cells through the use of chimeric antigen receptors (CAR-M) which targets antigens overexpressed on cancer cells. While CAR-macrophages showed success in increasing engulfment of solid tumor cells, they frequently resulted in trogocytosis (Morrissey 2018). Trogocytosis does not kill the cell, but instead strips the target antigen off the surface of cancer cells creating cells resistant to therapy. Despite the prevalence of trogocytosis in cancer cell-macrophage interactions, little is understood in regards to why macrophages trogocytose rather than phagocytose and how cancer cells prevent death via trogocytosis. We hypothesize that certain genes make cancer cells less vulnerable to death by macrophage trogocytosis. To test this hypothesis, we conducted a genome-wide CRISPR screen to identify genes involved in preventing trogocytosis lethality. Using HER2+ ovarian cancer cells and engineered Her2CAR macrophages, we have discovered that knocking down the CD47 “don't eat me” signal gene in ovarian cells enhances trogocytosis-mediated death, providing a positive control for our screen. Conducting a screen is likely to generate numerous hits, but we must account for background noise or other factors that could produce false positives. Thus, we will individually test genes identified during the screen to validate their roles in preventing trogocytosis-mediated death. Ultimately, we see garnering macrophage’s trogocytic behavior as a realistic and advantageous path to increase cell death during cancer immunotherapy treatment in the foreseeable future.