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 gen etic, 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 eli cit a protective T cell response. A continuous tumor cell line OM-2 ha s been established from a progressively growing mammary tumor and thre e 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 lym phocytes, although CD4(+) lymphocytes also appear to play a limited ro le. Cytotoxic T lymphocytes (CTLs) obtained from mice immunized with O M-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 l esser degree than OM-2, and do not lyse OM-10, in spite of the fact th at all cell lines express comparable levels of activated ras and MHC c lass 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 i mmune response does not appear to be directed to activated ras.