Tumor Specific CD4+ T-Cell Costimulation Through a Novel Receptor/Ligand Interaction

摘要

CD4+ T cells specific for tumor antigens have been less well characterized than CD8+ T cells. There appears to be two main reasons for this discrepancy; 1) CD8+ T cells isolated from tumor (tumor infiltrating lymphocytes; TIL) preferentially expand in the presence of anti-CD3 and IL-2, and 2) CD4+ T cells isolated from a tumor environment appear to be defective in signaling and therefore may not have the capacity to proliferate to tumor/tumor- associated Ag. We will attempt to bypass these limitations by using a novel approach to costimulate a tumor specific CD4+ T cell memory response. Recently, we found that CD4+ T cells isolated near the tumor sites of patients with% melanoma and head and neck cancer expressed the OX-40 receptor, but not cells in the periphery of these same patients. It is our hypothesis that these OX-40+ T cells were recently activated in vivo in response to tumor antigens. If a costimulatory signal could be provided to these OX-40+ T cells by the OX-40 ligand, then clonal expansion of CD4+ T cells specific tumor should occur. In this proposal, we will characterize OX-40 expression by human and mouse CD4+ T cells specific for breast cancer and attempt to expand them both in vivo and in vitro with MHCII+ tumors transfected with the OX-40 ligand, in essence making the tumor an antigen presenting cell capable of priming CD4 T cell immunity.