Immunity to murine breast cancer modified to express MUC1 in transgenic mice tolerant to human MUC1

The high incidence of breast cancer in women and the severity of the disease have stimulated a need for improved and novel forms of therapy. The product of the MUC1 gene has been identified as a breast cancer-associated antigen in breast cancer patients. The gene has been cloned and sequenced. Transgenic mice were prepared that express human mucin and are naturally tolerant to the molecule, providing a unique opportunity to investigate immunotherapeutic strategies in experimental animals that might eventually be applied to breast cancer patients. Mouse tumor cells expressing human MUC1 (E3 cells) were modified to secrete IL-2, IL-4, interferon-γ or IL-12 in order to evaluate the effect of cytokine-secretion on the cells' immunogenic properties in the MUC1 transgenic mice. The results indicated that modification of the breast cancer cells to secrete IL-12 augmented the cells' immunogenic properties in MUC1 transgenic mice and led to the development of resistance to non cytokine-secreting E3 cells. The T cell types activated for tumor rejection were determined by measuring the growth of E3-IL-12 cells in MUC1 transgenic mice depleted of CD4+, CD8+ or NK1.1 T cells. The rate of tumor growth and survival of the transgenic mice was compared with that of non-T cell depleted transgenic mice injected with equivalent numbers of E3-IL-12 cells alone. The results indicated that both CD4+ and CD8 + T cells were required to mediate the rejection of E3-IL-12 cells. Activated CD4+ and CD8+ T cells were detected in tumors undergoing rejection in MUC1 transgenic mice injected with E3-IL-12 cells. Immunization with MUC1 expressing breast cancer cells secreting IL-12 was also effective in inducing cellular immunity against MUC1. When cytotoxic T cell production specific for MUC1 was measured by in vitro analysis it confirmed the presence of T cell mediated cytotoxicity toward the MUC1 expressing tumors when MUC1 transgenic mice were immunized with E3-IL-12 cells. In contrast, no humoral immunity was generated against MUC1 in MUC1 transgenic mice. Our data obtained in a unique animal model system point toward an analogous form of therapy for breast cancer patients.