PROTECTIVE CELLULAR-IMMUNITY AGAINST A SPONTANEOUS MAMMARY-CARCINOMA FROM RAS TRANSGENIC MICE

Mammary carcinomas of v-Ha-ras transgenic mice closely resemble human breast cancer in their multi-step nature and in the requirement of genetic, hormonal and somatic mutational events for full-scale malignancy. We demonstrate that spontaneous breast cancers derived from v-Ha-uas transgenic FVB (H-2(q)) mice are highly immunogenic and that they elicit a protective T cell response. A continuous tumor cell line OM-2 has been established from a progressively growing mammary tumor and three sublines OM-10, OM-12 and OM-14 have been derived by in vivo passage of OM-2. All lines express the v-Ha-ras gene product and surface MHC class I. The parental OM-2 line is highly immunogenic and behaves like a regressor tumor. The regression of OM-2 is mediated by CD8(+) T lymphocytes, although CD4(+) lymphocytes also appear to play a limited role. Cytotoxic T lymphocytes (CTLs) obtained from mice immunized with OM-2 show MHC class I-restricted, specific T cell cytotoxicity against OM-2 hut not normal fibroblasts derived from ras transgenic mice. The anti-OM-2 CTLs lyse the OM-2 sublines OM-12 and OM-14, although to a lesser degree than OM-2, and do not lyse OM-10, in spite of the fact that all cell lines express comparable levels of activated ras and MHC class I. Our studies represent the first analysis of protective T cell response to breast cancer and demonstrate that contrary to expectation, the spontaneous breast cancers are highly immunogenic and that the immune response does not appear to be directed to activated ras.