Anti–HER-2/neuImmune Responses Are Induced before the Development of Clinical Tumors but Declined following Tumorigenesis in HER-2/neuTransgenic Mice

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Abstract
HER-2/neu oncogene products have been implicated as a potential target of T cell–mediated immune responses to HER-2/neu–induced tumors. Using HER-2/neu transgenic mice (oncomice), we investigated whether, and if so how, anti–HER-2/neu immune responses are induced and modulated in these oncomice from birth to tumor initiation. Female oncomice carrying the activated HER-2/neu oncogene displayed apparent hyperplasia in mammary glands at 10 weeks of age and developed mammary carcinomas around an average age of 26 weeks. Unfractionated spleen cells from 10- to 15-week-old oncomice that were cultured without any exogenous stimuli exhibited cytotoxicity against the F31 tumor cell line established from an HER-2/neu–induced mammary carcinoma mass. The final antitumor effectors were a macrophage lineage of cells. However, this effector population was activated, depending on the stimulation of oncomouse CD4+ T cells with oncomouse-derived antigen-presenting cell (APC) alone or with wild-type mouse APC in the presence of F31 membrane fractions, suggesting the presence of HER-2/neu–primed CD4+ T cells and HER-2/neu–presenting APC in 10- to 15-week-old oncomice. These antitumor cytotoxic responses were detected at ∼5 weeks of age and peaked at age 10 to 15 weeks. However, the responses then declined at tumor-bearing stages in which the expression of target proteins could progressively increase. This resulted from the dysfunction of CD4+ T cells but not of APC or effector macrophages. These results indicate that an anti–HER-2/neu CD4+ T cell–mediated immune response was generated at the pretumorigenic stage but did not prevent tumorigenesis and declined after the development of clinical tumors.