This application proposes a 5-year training program which will provide a mechanism for the principle investigator, Dr. Lance U'Ren, to transition into a successful independent researcher in the field of cancer immunology. Dr. U'Ren is a veterinarian who will complete his Ph.D. training at Colorado State University in December 2006. Dr. U'Ren's career objective is to become a biomedical scientist who can use his veterinary and research training to develop novel immunotherapies that translate into clinical medicine. The proposed training will be conducted at National Jewish Medical Research Center, which is home to one of the best immunology training environments in the country. Dr. U'Ren will be mentored by Drs. Jill Slansky and Philippa Marrack, who will provide a superb training environment in T cell immunology. Dr. Slansky's research focuses on mechanisms to improve T cell responses to tumors. Dr. Marrack is a distinguished professor and a Howard Hughes Medical Institute Investigator who is internationally renowned for her contributions to the understanding of T cell immunity. Tumor-infiltrating lymphocytes (TILs) usually contribute to a positive prognosis for cancer patients. However, the antitumor T cell response is often tempered in larger primary tumors and metastatic lesions. The vascularization of these lesions is poorly organized resulting in hypoxic microenvironments. The overall research objective of this proposal is to determine what influence tumor hypoxia has on T cell functions and if alteration of the T cells response to hypoxia improves antitumor immunity. Using a mouse model for colon cancer with defined antigens and corresponding T cells, Dr. U'Ren will 1) Determine if increased protein expression of the transcription factor, hypoxia-inducible factor-1 alpha (HIF-1 alpha), in TILs improves T cell function, migration, and antitumor immunity. 2) Determine if high affinity engagement of the T cell receptor will improve migration of TILs into hypoxic tumor regions by signaling through HIF-1 alpha. By understanding the effects of hypoxia on TILs, cancer vaccines can be rationally modified to enhance antitumor immunity. The career development award proposed herein will improve our knowledge of how T cells interact with the tumor microenvironment, provide Dr. U'Ren with intensive training by the world class scientists at NJMRC, and ultimately provide for his transition into a successful independent investigator. ? ? ?