Grant: Operating Grant

Natural killer (NK) cells are cells of the immune system that play a critical role in the protection of humans against cancers such as leukemias and lymphomas, as well as against viral infections. This activity is especially dependent on the presence of a family of molecules expressed at the surface of NK cells, named the SLAM family of receptors. SLAM family receptors stimulate the ability of NK cells to kill cancer cells, through a molecular mechanism requiring a group of small molecules located inside the NK cells termed the SAP family of adaptors. One of the SAP family adaptors, SAP, is mutated in a human disease named X-linked lymphoproliferative disease, which is characterized by a high frequency of lymphomas. Our recent work uncovered that, in cells lacking SAP, the SLAM family receptors are converted into receptors that suppress the ability of NK cells to respond to cancer cells. This change likely explains in significant part why NK cells from XLP patients fail to protect against lymphomas. Over the past years, there has been increasing interest towards using NK cell-directed therapies in an adjuvant setting for anti-cancer treatment. However, a better understanding of NK cell regulation is needed to ensure that promising breakthroughs are made in this area. In this proposal, we want to understand better how SLAM family receptors control the ability of NK cells to kill tumor cells. We believe that the studies proposed will not only improve our understanding of the functions of SLAM family receptors, but will also help identify molecules that could be targeted to develop new treatments to control tumor cells and, perhaps, virus-infected cells.