Grant: China-Canada Joint Health Research Initiative

Cytotoxic lymphocytes, namely natural killer (NK) cells and CD8+ T cells, play a key role in the ability of the host to control the growth of cancer cells. However, though a multitude of mechanisms, cancer cells frequently escape immune surveillance and produce clinically-apparent cancers that have devastating effects. Considering these notions, much effort has been devoted over the past decades towards understanding and, hopefully, improving immune surveillance against cancer cells, in order to halt or reverse tumor progression in humans. Previously, we showed that the SLAM-SAP pathways play a key role in the ability of NK cells to kill malignant hematopoietic cells, but not non-hematopoietic cells, in vitro. This feature relates to the fact that hematopoietic cells, but not non-hematopoietic cells, express ligands for the SLAM family receptors, which trigger the functions of SAP family adaptors. In a related way, others subsequently demonstrated that the SLAM-SAP pathways are necessary for the capacity of CD8+ T cells to kill abnormal hematopoietic cells, but not non-hematopoietic cells, in vitro. Thus, as a result of their roles in NK cells and CD8+ T cells, the SLAM-SAP pathways seem to have pivotal functions in the ability of immune cells to prevent hematopoietic cell-derived tumors. To validate the physiological importance of this mechanism, it is important to examine the effects of the SLAM-SAP pathways on tumorigenesis in vivo. Here, we will elucidate the role and potential therapeutic usefulness of the SLAM-SAP pathways in anti-tumor immunity in vivo. Using mouse models, we will: 1) evaluate the role of the SLAM-SAP pathways in immune surveillance against hematopoietic cancers in vivo. 2) Test the possibility that enforced expression of the SLAM family ligand, CRACC, on hematopoietic tumors could improve anti-tumor immunity in vivo. And 3) examine the therapeutic usefulness of ectopically expressing SLAM family ligands on non-hematopoietic cancers.