Breast cancer is the primary cause of death in women. Specific immuno-preventive modality for women with high risk of developing breast cancer is lacking. The goal of this proposed study is to test the hypothesis that effective anti-tumor immune response which prevents mammary tumorigenesis can be generated in the preneoplastic lesions by modifying the immune cell composition of the lesions and by providing lymphokines in situ with gene-modified mammary fibroblasts. These studies will be performed in BALB/c preneoplastic hyperplastic alveolar nodules (HAN) which give rise to spontaneous tumors at a predicted frequency and latency period. Specifically, we will (1) modify the immune cell composition in HAN to enhance the anti-primary tumor immune reactivity, (2) continue characterization and development of genetically engineered mammary stromal fibroblasts capable of producing interleukin-2 or interferon- , and (3) determine the phenotypes and activities of mammary lesion infiltrates and the efficacy of preventing tumorigenesis with in situ lymphokine production. These studies are based on our previous findings that at strongly immunogenic tumors arise from preneoplastic hyperplastic alveolar nodules (HAN) at high frequencies (70% in 10 months for C4 HAN). Immunogenicity of these tumors was demonstrated in tumor cell sensitized mice by specific transplantation rejection and cell-mediated cytotoxicity. Infiltrates from the spontaneous tumors, however, do not mediate direct cytotoxicity but inhibit tumor growth in Winn assay. Systemic treatment of C4 HAN bearing mice with recombinant interleukin-2 greatly enhanced NK activity in the spleens and the HAN infiltrates, but did not potentiate anti-tumor T cell activity and had no protective effect against tumorigenesis. To enhance the immune reactivity against spontaneously arising tumors, lymphokines will be generated locally in the mammary fat pads where HANs grow. The immune cell composition which is required to inhibit tumor growth in lymphokine-bathed HAN will be determined. IL-2 secreting primary mammary stromal fibroblasts and mammary tumor cells have been produced by retroviral transduction for the proposed studies. These studies will provide useful information toward the design and evaluation of tumor prevention strategies.
