IMMUNITY TO MELANOMA WITH IL-2-SECRETING ALLOGENEIC CELL

点击翻译按钮获取中文摘要

In spite of the fact that they express immunogenic determinants, B16 melanoma cells grow progressively in immunocompetent C57BL/6 mice (H-2b). The mechanism of "escape" is not established. Since cytotoxic T lymphocytes are known to recognize an extraordinarily wide array of small peptides (in the context of histocompatibility class I), including neoantigens associated with malignant cells, it may be that the growth of antigeneic tumors results from a failure of immune recognition, not from the absence of tumor associated determinants. An understanding of the cellular "defect" that enables tumor cells to grow in immunocompetent recipients could have important implications for the specific immunotherapy of cancer. As an experimental approach, we used transfection to construct IL-2-secreting, allogeneic mouse fibroblasts that express melanoma associated antigens. We then tested the cells' immunogenic properties in terms of their ability to elicit an anti melanoma immune response in mice syngeneic with the tumor. The construct was prepared by transfecting genomic DNA from B16 cells (H-2b) into LM cells (H-2k) which are allogeneic with C57BL/6 mice. Colonies of transfected cells expressing melanoma- associated determinants were isolated, and then infected with an expression competent plasmid carrying the gene for IL-2. In our experiments, C57BL/6 mice rejecting the IL-2-secreting, melanoma antigen-positive allogeneic mouse cells developed cellular immunity to the melanoma. This immunity exceeded that following immunization with non-IL-2-secreting constructs, or with B16 cells. The objectives of the proposal are to determine the specific cell types activated for rejection of B16 melanoma following immunization of C57BL/6 mice with the IL-2-secreting cell constructs, and compare them with cell types activated following immunization of mice with constructs that lack one or more of the immunogenic properties. In addition, we plan to determine if exogenous IL-2 can substitute for the direct cell-to-cell (paracrine) transfer of IL-2 in the induction of an anti melanoma immune response. Finally, we plan to determine if immunizations of tumor-bearing mice with the IL-2-secreting constructs leads to increased survival.