Role for alpha2-Macroglobulin in Immune Responses and Cancer Immunotherapy

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DESCRIPTION (provided by applicant): Alpha2 macroglobulin (a2M) shares its cell surface receptor CD91 with the immunogenic heat shock proteins. Based on this observation we have tested and shown that mice immunized with a2M elicit T cell responses to peptides that are chaperoned by it. Preliminary studies presented for this project have shown that the engagement of CD91 by a2M and the ability of a2M to chaperone peptides are two key properties necessary for elicitation of the immune response. No other mechanistic procedure has been provided and the aims of this project are designed to understand first the interaction of these autologous proteins with antigen presenting cells to initiate the immune response and second what the physiological relevance of these proteins are in the elicitation of immune responses. A part of this project will test the harnessing of these immune responses for vaccine design targeting cancer and infectious disease. My primary short term goals also include studying a2M in context of other CD91 ligands such as the HSPs, and their various roles in cross-presentation and cross-priming. In this regard we have developed and published numerous tools necessary for this work: purification procedures for a2M and peptide antigens, procedures for the creation of a2M-peptide complexes, tumor rejection models in both prophylaxis and therapy and currently preparing CD91 deficient knock out mice. A long term goal is the translation of the basic research of my lab into clinical applications for the treatment of cancer and an understanding of why these self proteins are immunogenic in the first place. Our laboratory and office are located on the 10th floor of the Biomedical Science Tower of the University of Pittsburgh. The laboratory has 600 sq ft of space and is fully equipped for cellular immunology and molecular biology research and for all the projects described in this project. It is contiguous with other laboratories with the Department of Immunology and we have access to common use equipment and vast research support facilities. A pathogen-free animal facility run by the University is available in the same BST building and is AAALAC accredited. RELEVANCE: The studies described in this project, when completed, will provide an insight to the mechanism by which alpha2-macroglobulin elicits T cell immune responses and how this response can be harnessed to generate vaccines against cancer and infectious agents. These studies will provide preliminary data leading to clinical trials in cancer patients with autologous alpha2-macroglobulin-based vaccines.