The discovery of tumor antigens and specific anti-tumor immune responses has raised hopes for the immunotherapy of tumors. However, animal models as well as clinical trials strongly suggest that the anti-tumor immune response is tolerized in a tumor-bearing host. The tolerance can be mediated by a variety of immunosuppressive effects relating to tumor products, suppressor cells and serum suppressive factors. Therefore, immunotherapy efforts, particular those to immunize patients with tumor vaccines, have to contend with this immunosuppression in order to obtain efficient anti-tumor immune responses to eliminate tumors. Our preliminary studies indicate that many human and mouse tumor cells express neuronal repellent Slits, a group of molecules that inhibit leukocyte migration. Recent studies in our laboratory have indicated that Slits inhibit the migration of dendritic cells and suppress immune responses. It is a common feature that leukocytes fail to infiltrate tumors. Convincing data exhibit that leukocyte infiltration in tumors is associated with the prognosis of patients and is an indicative parameter for the clinical response of immunotherapy. Our hypothesis is that blocking tumor derived Slits will enhance the infiltration of immune cells in tumors and improve the efficiency of anti-tumor immunotherapy. The hypothesis will be examined in three specific aims. (1) To detect the production and activity of Slits in human tumors. The result will provide evidence for the effect of Slit mediated immunosuppression in tumor patients. (2) To examine the role of tumor derived Slits in the induction of anti-tumor immune responses.
This aim will identify whether blocking Slits breaks down tumor mediated immunosuppression on the induction of immune responses and enhances the efficiency of tumor vaccination. (3) To determine the effect of Slits in the rejection of established tumors by immunotherapies. We will examine whether blocking tumor derived Slits improves the rejection of established tumors by dendritic cell based immunotherapy and adoptive transfer of immune T cells. The ultimate goal of the proposal is to identify tumor derived Slits as a new target in the development of tumor immunotherapy and to establish protocols for enhancement of anti-tumor immune responses. The outcome may provide valuable information for improving the efficiency and clinical response of tumor immunotherapies.
