EPIDERMAL ANTIGEN-PRESENTING CELLS AND TUMOR IMMUNITY

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It has been demonstrated in certain strains of mice that, when ultraviolet radiation (UVR) is employed to induce cutaneous malignancies, specific immunologic changes occur in the animal as a direct consequence of UVR exposure and that these alterations in immune function serve to protect the tumor from immunologic destruction and allow its growth. It has been hypothesized that this may occur due to UVR-induced perturbations in Langerhans cells (LC) that prevent presentation of tumor associated antigens (TAA) for activation of immunologic effector mechanisms while allowing presentation of TAA by certain non-LC epidermal elements and/or UVR-altered LC for induction of immunologic down-regulation. This hypothesis is supported by data showing that, after exposure of LC to UVR in vitro, priming of mice provides a tolerogenic signal (if administered intravenously) rather than an immunogenic signal. Also, non-LC, epidermal elements, including Thy 1(+) dendritic epidermal cells (EC) and high-density : I-A+ EC, can present haptens for down-regulation of immunity with or without exposure to doses of UVR that alter LC function. However, direct functional evidence of a role for LC in tumor immunity is lacking. The experiments proposed herein will address this question. The objective of these studies is to examine the ability of epidermal antigen presenting cells (APC) to present TAA on murine skin cancer lines for in vivo and in vitro immune responses. These studies will examine whether certain keratinocyte and lymphocyte-derived cytokines modulate the ability of epidermal APC to perform this function. This is of interest since the cytokine microenvironment of the LC in situ may regulate, in part, its function. The ability of UVR to modify presentation of TAA by epidirmal APC will be specifically examined. In addition, the ability of specific non-LC epidermal elements and UVR-perturbed low density I-A+ Langerhans cells to present TAA for immunologic down-regulation will be examined. In order to examine possible mechanisms of UVR perturbation of APC function, well-defined systems of protein antigen processing and presentation will be utilized. Experiments will examine the possible roles of specific UVR-induced changes in APC-membrane biology in UVR-induced alterations in the function of certain APC including LC. A more complete understanding of the mechanisms by which the immune system interacts with developing cutaneous malignancies and the mechanisms by which cytokines and UVR may affect these process might have currently unforseen therapeutic implications.