The Role of Lymphoid Environments in Guiding T Cell Migration

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DESCRIPTION (provided by applicant): Immunization with dendritic cells (DCs) has exciting potential as a therapeutic for the treatment of cancer. DCs are attractive candidates due to their ability to stimulate naive T cells leading to T cell mediated tumor cell lysis. Murine bone marrow derived DCs (BMDCs) provide an important model to examine the immune response under controlled conditions limiting confounding issues such as immunomodulatory factors and antigen (Ag) persistence present in models of T cell activation by pathogens. The successful use of BMDCs as a therapeutic relies not only on the proper generation of T cells, but also their migration to diseased sites. The route of BMDC immunization dictates the site of T cell priming and recent data from this lab supports the importance of the site of T cell priming as the route of BMDC immunization influences the ability to protect against melanoma growth. While several reports have examined the role of adhesion proteins and chemokine receptors in guiding T cell migration, the role of these proteins in T cell migration in the context of a tumor is unknown. The studies in this proposal seek to evaluate the homing receptors on CD8 T cells that mediate tumor infiltration. In relation to this is how the site of CDS T cell activation by tumor-derived Ag presented by endogenous DCs and exogenous BMDCs influences the expression of homing receptors by CDS T cells. In addition, the expression of homing receptors on CDS T cells induced by BMDCs in the presence of a tumor will also be explored to understand any possible influence a tumor may have on BMDC induced T cell migration. These studies will test the hypothesis that BMDC immunization induces unique homing receptors on CDS T cells compared to activation by tumor-derived Ag presentation and altering the route of BMDC immunization to target different lymphoid compartments influences the ability of CDS T cells to infiltrate anatomically distinct tumors. The Specific Aims of this proposal are 1) To determine the CDS T cell homing receptor profile on activated CDS T cells that infiltrate tumors growing in distinct anatomical locations and examine the necessity of these homing receptors to mediate CDS T cell infiltration of anatomically distinct tumors. 2) To analyze the induction of homing receptors on CDS T cells activated by tumor-derived Ag presented by endogenous DCs in distinct lymphoid compartments and to determine how this compares to or is altered by exogenous immunization with BMDCs.