Innate immunosurveillance of breast cancer

Dr Makrigiannis will be studying the role of the innate immune system in the prevention of breast cancer. Specifically, he will test whether a type of white blood cell a called natural killer cell is able to detect and destroy breast cancer cells. Dr Makrigiannis has shown that natural killer cells prevent lymphoma development by using Ly49 receptors in mice. He now wishes to see if this is also true for breast cancer. If natural killer cells are found to play a role in breast cancer then there are ways to increase their effectiveness by administering specific drugs. This research will potentially allow researchers to use the body's own weapons in eradicating breast cancer.Natural killer (NK) cells roam the body and look for cells that have become infected or cancerous. NK cells are able to recognize healthy versus unhealthy cells using 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. These researchers have preliminary data that in mice which are genetically deficient in class I MHC receptors, lymphomas arise earlier and the tumour cells tend to be missing class I MHC. While many genes to date have been implicated in breast cancer induction and progression, the role of class I MHC mutation in this cancer is unknown. The research team will apply their model system to breast cancer and to determine if class I MHC modulation is required for breast cancer development.All cancers must find ways to circumvent the cells of the immune system, including natural killer (NK) cells, in order to survive. The researchers have strong preliminary data using gene-deficient mice that class I MHC receptors on NK cells, called the Ly49, are needed to stop lymphoma induction. They are now applying this knowledge and technique to test whether class I MHC modulation in breast cancer is important. They have produced Ly49-deficient mutant mice and will cross these to various genetic models of breast cancer in mice and measure 1) time of breast cancer onset; and 2) specific mutations in class I MHC and associated genes in breast cancers. Their objectives are to 1) determine if the loss of Ly49 affects breast cancer incidence in mice; 2) determine the type and nature of class I MHC gene mutations in breast cancer cells; and 3) determine if blocking the inhibitory Ly49 results in improved NK cell function against breast cancer cells.Breast cancer is a leading killer of women in Canada and around the world. If it can be shown that class I MHC is a target for mutation during the induction and progression of breast cancer then it would be a simple matter to check for a correlation between class I MHC levels on early cancers and survivability. Thus, this study may be able to provide a new prognostic indicator for cancer of the breast. In addition, determining if natural killer cells play a role in surveillance against breast cancer will now provide a new cellular target for immune system-boosting therapies or even possibly adoptive immunotherapy. Natural killer cells are the targets of new clinical trials testing cancer therapies, but these are mainly focused on lymphomas and leukemias. However, there is no reason why natural killer cells cannot also be used to kill carcinomas of other tissues, including the breast.