The candidate, Dr. Ravindra Uppaluri, is a faculty member in Otolaryngology at Washington University. Dr. Uppaluri's u l timate goal is to become an independent investigator studying the interaction of the immune system and head and neck malignancies. To achieve this goal he joined the laboratory of Dr. Robert Schreiber to pursue training in tumor immunology. The training plan includes a dedicated mentor, an intensive laboratory experience, and additional course work and seminars to complement the candidate's development. Dr. Schreiber's laboratory has demonstrated the existence of an interferon gamma (IFN-gamma) and lymphocyte- dependent tumor surveillance system that is operative in preventing many types of mouse tumors. This model requires the action of endogenously produced IFN- gamma. Two actions of IFN-gamma have been proposed: first, its capacity to regulate immunogenicity of tumors; and second, its capacity to force the tumor to produce angiostatic chemokines such as IP-10, Mig, and I-TAC. The purpose of this proposal is to critically test whether IFN-gamma-induced angiostasis plays an obligate role in mediating tumor surveillance and to establish the temporal relationship between IFN-gamma's abilities to effect angiostasis versus immunogenicity. To achieve this goal, the project will pursue three specific aims.
In Specific Aim 1, the effects of IP-10, Mig and I-TAC on IFN- g a m m a-sensitive and insensitive tumor growth will be assessed both individually and collectively by transplanting tumors in mice that have been treated with monoclonal antibodies to block IP-10, Mig and I-TAC.
Specific Aim 2 will address the effects of enforced and inducible expression of IP-10 on tumor growth.
Specific Aim 3 will address the requirement of lymphocytes for tumor growth and regression in the context of IP-10 and define the relative contribution of angiostasis in immunization of the mouse to tumor. This work should provide a clear picture of events that lead to host defense against cancer.
