The Role of Non-Hematopoietic Cells in Tumor Tolerance Induction

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DESCRIPTION (provided by applicant): Candidate Goals and Career Development Plan: The candidate is a thoracic surgeon with the ultimate goal of becoming an independent investigator in the field of tumor immunology. Despite the recent description that the adaptive immune system is important for tumor immune surveillance and elimination, clinically evident tumors develop in individuals with an intact immune system and display tumor specific tolerance. The candidate's goal is to develop the fund of knowledge and skills necessary to study tumor specific tolerance induction. The candidate will achieve this over a period of five years by: 1) studying the role of non-hematopoietic stromal cells in the generation of tumor associated regulatory T cells; 2) evaluating the role of tumor MHC Class II expression on the tumor immune response and; 3) gathering data necessary to transition to independent investigation. Environment: The environment at Washington University in St. Louis is exceptional with multiple investigators with expertise in various aspects of immunology. The candidate's sponsor specifically is an internationally recognized expert in tumor immunology. His work on tumor immunoediting has played a pivotal role in advancing the understanding of tumor immune surveillance as well as escape mechanisms that allow for tumor growth. The mentor's laboratory studies multiple aspects of tumor interaction with the adaptive immune system and is ideal for achieving the candidate's goals. Research Proposal: The primary aim of this grant is to evaluate the role of non-hematopoietic cells in the generation of tumor specific regulatory T cells. Preliminary data indicate that the number of CD4+Foxp3+ regulatory T cells increases within tumor bearing tissues and that some non-hematopoietic parenchymal cells express surface MHC Class II and are able to take up, process, and present foreign antigen to CD4+ T cells. Based on this as well as the candidate's previously published data it is hypothesized that presentation of tumor associated antigen by parenchymal cells leads to the generation of regulatory T cells and induction of tumor specific tolerance. The specific aims outlined in this proposal focus on evaluating this hypothesis using multiple in vitro and in vivo models. These studies will serve to define the role of non-hematopoietic cells in the induction of immunologic tolerance to solid tumors.