Innate immune evasion by the cancers of the blood and breast

Dr Andrew Makrigiannis and his colleagues will study the role of a type of innate immune cells ? natural killer (NK) cells ? in the detection and elimination of aberrant cells that give rise to blood and breast cancers. NK cells can detect tumour cells and delay the development of lymphoma and mammary tumours. However, many tumour cells have learned to evade detection. The research team will investigate how cancer cells evade detection by NK cells. NK cell function can be modulated by administering specific drugs. This study will explore strategies to enhance NK cell function in conjunction with existing conventional therapies for a more favourable therapeutic response and long-term protection in cancer patients. NK cells roam the body and look for cells that have become infected or cancerous. NK cells are able to distinguish healthy from unhealthy cells via receptors for class I MHC, a marker of health found on all normal cells. Whether class I MHC mutations contribute to cancer development has long been a contentious issue. Dr Makrigiannis and his team have preliminary data that in mice that are genetically deficient in class I MHC receptors, lymphomas and mammary tumours arise earlier and the tumour cells tend to be missing class I MHC. This could be due to mutations in the class I MHC and/or MHC-associated genes. Tumour cells can target the MHC recognition system to evade detection by the immune cells. While many genes to have been implicated in cancer induction and progression, the role of class I MHC mutation is unknown. The researchers wish to apply their class I MHC receptor deficient model system to cancers. They will also determine the mechanisms of class I MHC receptor immune evasion by the cells that give rise to cancers. The rationale for this project is that cancers must circumvent the cells of the immune system, including NK cells, in order to survive. The researchers have shown using gene-deficient mice that class I MHC receptors on NK cells can detect lymphoma and mammary tumours. Tumour cells have evolved ways to evade this detection system. Understanding the mechanisms of class I MHC receptor evasion by tumour cells, including cancer stem cells, will facilitate the design of effective cancer immunotherapies. This study will make use of the team's unique class I MHC receptor?deficient mouse model to study tumour induction, tumour growth and mutations in MHC-associated genes that may help the tumour cells to evade detection by the NK cells.The objectives of this research are to:1. Define the role of class I MHC receptor immune evasion by cancer stem cells in blood and breast cancers.2. Determine the genetic mechanisms of class I MHC receptor immune evasion using bioinformatics.3. Test the therapeutic feasibility of disrupting the recognition of class I MHC by its receptor in breast cancer. Cancers are the leading cause of death among Canadians and around the world. Mutations in many genes have been implicated in cancer induction and progression. This research will determine if class I MHC is a target for mutation during the induction and progression of cancer. This research could have an impact on both cancer prognosis and therapy. An correlation between class I MHC levels on tumour cells, cancer progression and survivability will provide a new prognostic indicator for cancer patients. In addition, defining the role of NK cells in the detection and elimination of the elusive cancer stem cells will provide a new cellular target for cancer immunotherapy. NK cells are the targets of new clinical trials testing cancer therapies, which are mainly focused on lymphomas and leukemias. This study will pave the way for the use of NK cell?based immunotherapies in clinical trials involving breast cancer patients as well.