Find tumor immune evasion strategies by cellular barcoding

Cancer is a leading cause of death worldwide, accounting for 8.8 million deaths in 2015. One of the most recent and highly successful advances in anti-cancer treatment is cancer immunotherapy. As cancer patients are frequently suffering from immunosuppression, immunotherapy aims at re-activating the immune system. Natural killer (NK) cells are at the forefront of the bodys anti-tumor defense capable to directly kill tumor cells and to activate other immune cells. Novel therapies including the infusion of pre-activated NK cells into tumor patients have shown extraordinary performance. However, certain limitations curtail the success story. Malignant cells are highly adaptable to their environment and capable to efficiently evade from immune surveillance. The concept of immunoediting describes the phenomenon that tumors change their appearance and become immune-resistant upon constant pressure imposed by the immune system. This concept has been shown in experimental models such as chemically-induced tumors, but whether and how it applies in other malignancies is still a matter of debate. In the present project we hypothesize that immunoediting takes place in natural tumors. There is unequivocal evidence for the importance of NK cells in the fight against leukemia. We thus choose leukemia as a model system to address whether NK cell-mediated immunoediting is taking place. The design of our study will allow two potential scenarios to be distinguished: (i) NK cells are able to kill most tumor cell clones but spare the few pre-existing resistant sub- clones (clonal selection) or (ii) NK cells shape tumors by classical immunoediting. We further aim to determine the underlying molecular mechanisms for tumor evasion from NK cell- mediated eradication. This is made possible by using a cellular barcoding system that allows tracking of single leukemic cells in mice. The combination of cellular barcoding and next generation sequencing enables us to determine changes causing immune-resistance and tumor outgrowth. A better understanding of the molecular mechanisms underlying tumor immune evasion is the first step to utilize the full potential of NK cells in anti-tumor therapy. Ultimately, this study will pave the way for new therapeutic approaches to treat tumors that have successfully evaded the immune system.