T Cell Regulation of Cutaneous Malignancy

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): There is intensifying interest in tumor immunosurveillance and the prospect of cancer immunotherapy. This is principally founded on the concept that a developing tumor can be recognized by systemic T cells that will kill it either directly or via TH1-mediated cytokine effects. However, this view largely ignores the potential involvement of local T cells that are resident at many sites of carcinoma development, and it fails to accommodate the increasing appreciation of the complexity of the cell-mediated immune response that can involve a variety of regulatory as well as effector T cells. Therefore, we have set out to understand the individual and distinct contributions of defined components of the immune system to the regulation of cutaneous malignancy. The work builds on recently published experiments using murine models of carcinogenesis that collectively have exposed the complexity of the immune response and indicate a variety of issues that need to be considered in our understanding of immunosurveillance and the design of immunotherapy strategies. The hypothesis proposed is that various subsets of alpha-beta and gamma-delta T cells act differentially to regulate cutaneous malignancy. The major goals of the proposed studies are to identify those specific T cell subsets, begin to elucidate their mechanism(s) of action, and demonstrate critical effects of the immune system on tumor development previously revealed by altered gene expression profiles of tumors developing in hosts of different immunocompetence. To achieve these goals, the following four (4) specific aims are proposed: Aim 1 -Determine whether Vgamma5+ DETC alone are sufficient to mediate protection against cutaneous malignancy, and the degree to which systemic recirculating gamma-delta+ T cells add or subtract from tumor protection. Aim 2 -Determine the relative anti- and pro-tumor properties of specific subsets of alpha-beta T cells as determined by their effects on tumor development (i.e. papilloma formation) and progression to carcinoma. Aim 3 - Assess the role of several key immune effector molecules (IFNgamma, IL-10, FasL, and perforin) in gamma-delta and alpha-beta T cell regulation of cutaneous T cell deficient mice following selective repopulation of T cell deficient mice with various subsets of T cells from mice genetically deficient in immune effector molecules. Aim 4 - Analyze in vivo the biological effects of plasmid driven over-expression vs. inhibition of expression (using RNAi) of collapsin, osteopontin and syndecan-1 by PDV tumor cells in the presence and absence of immune components.