Immune mechanisms serve to protect individuals against neoplasia. Suppressor T-cell (Ts-cell) mechanisms, however, allow many malignancies to escape immunologic rejection. Therefore, the delicate balance between T-cell mediated tumor-immune and Ts-cell dominated immunoregulatory responses ultimately determines whether a malignant tumor is rejected or allowed to grow. The goal of the project specified in RFA #87-CA-30 is to develop therapies to manipulate the suppresor arm of the immune system to enhance the destructive immunologic attack on malignant tumors. Immunotherapy treatment of cancer is an attractive clinical approach, since tumor-specific immune response will both eliminate malignant cells without damaging normal tissues, as well as extend immune protection against the growth of metastatic foci and recurrence of the neoplasm. We have studied the immunobiology of ultraviolet radiation (UVR) carcinogenesis for the past decade. Our contributions have helped identify the role played by Ts-cells in the emergence and growth of UVR-induced skin tumors. We now have cloned Ts-cell lines with defined phenotypic and functional properties that are shared by Ts-cells in UVR-exposed mice. Since these Ts-cells are active prior to the detection of neoplasia and possess functional specificity for a shared tumor antigen, they allow for the emergence and growth of most UVR-induced skin tumors. Using these defined Ts-cell lines we intend to identify the mechanisms involved in the regulation of anti-tumor immune responses and apply this information to the design of preclinical models for developing the therapies requested in RFA #87-CA-30. To achieve this objective, we will: 1) determine the mechanisms of induction of Ts-cells by UVR: 2) define the mechanism(s) by which UVR-induced Ts-cells inhibit tumor-immune rejection responses; and 3) identify therapeutic agents and develop treatment that cause tumor regression by inhibiting Ts-cell function. We will accomplish this by: 1) isolating specific UVR induced alterations and defining their role in favoring the elicitation of either effective cell-mediated tumor rejection or sponses, or Ts-cell mediated immunoregulatory respones; 2) determining the target of UVR induced Ts-cell suppression, i.e., whether a component of the cellular interactions required for an effective immune response, or the neoplasm itself through a direct or indirect mechanism; and 3) identifying agents that inactivate cloned Ts- cells and applying them in various in vivo tumor induction and growth models to establish their efficacy in causing tumor regression.
| Roberts, L K; Jun, B D; Gilhar, A et al. (1989) Effect of ultraviolet radiation on Ia expression by keratinocytes. Photodermatol 6:275-86 |
| Jun, B D; Law, M Y; Daynes, R A et al. (1989) Splenic contribution to the recovery of ATPase/Ia+ epidermal cells in the skin of mice after exposure to ultraviolet radiation. Reg Immunol 2:225-35 |
