Abstract
In Simian virus 40 (SV40) transgenic BALB/c WAP-T mice tumor development and progression is driven by SV40 tumor antigens encoded by inducible transgenes. WAP-T mice constitute a well characterized mouse model for breast cancer with strong similarities to the corresponding human disease. BALB/c mice mount only a weak cellular immune response against SV40 T-antigen (T-Ag). For studying tumor antigen specific CD8+ T-cell responses against transgene expressing cells, we created WAP-TNP mice, in which the transgene additionally codes for the NP118-126-epitope contained within the nucleoprotein of lymphocytic choriomeningitis virus (LCMV), the immune-dominant T-cell epitope in BALB/c mice. We then investigated in WAP-TNP mice the immune responses against SV40 tumor antigens and the NP-epitope within the chimeric T-Ag/NP protein (T-AgNP). Analysis of the immune-reactivity against T-Ag in WAP-T and of T-AgNP in WAP-TNP mice revealed that, in contrast to wild type (wt) BALB/c mice, WAP-T and WAP-TNP mice were non-reactive against T-Ag. However, like wtBALB/c mice, WAP-T as well as WAP-TNP mice were highly reactive against the immune-dominant LCMV NP-epitope, thereby allowing the analysis of NP-epitope specific cellular immune responses in WAP-TNP mice. LCMV infection of WAP-TNP mice induced a strong, LCMV NP-epitope specific CD8+ T-cell response, which was able to specifically eliminate T-AgNP expressing mammary epithelial cells both prior to tumor formation (i.e. in cells of lactating mammary glands), as well as in invasive tumors. Elimination of tumor cells, however, was only transient, even after repeated LCMV infections. Further studies showed that already non-infected WAP-TNP tumor mice contained LCMV NP-epitope specific CD8+ T-cells, albeit with strongly reduced, though measurable activity. Functional impairment of these 'endogenous' NP-epitope specific T-cells seems to be caused by expression of the programmed death-1 protein (PD1), as anti-PD1 treatment of splenocytes from WAP-TNP tumor mice restored their activity. These characteristics are similar to those found in many tumor patients and render WAP-TNP mice a suitable model for analyzing parameters to overcome the blockade of immune checkpoints in tumor patients.
Highlights
Breast cancer is the leading cause of cancer deaths among women in industrialized countries and despite improved diagnostic and therapeutic options accounts for 23% of the total cancer cases and 14% of cancer deaths [1]
NP8 mice are non-reactive against Simian virus 40 (SV40) T-Ag, but highly reactive against the immunedominant lymphocytic choriomeningitis virus (LCMV) NP-epitope
The lack of protection shows that even immunization with highly immunogenic vaccinia virus (VV)-941T cannot induce T-Ag specific protective immunity in NP8 mice, indicating that transgenic expression of weakly immunogenic T-Ag interferes with induction of T-Ag specific cytotoxic T lymphocyte (CTL)
Summary
Breast cancer is the leading cause of cancer deaths among women in industrialized countries and despite improved diagnostic and therapeutic options accounts for 23% of the total cancer cases and 14% of cancer deaths [1]. For a detailed study of mammary carcinogenesis, and of immune reactions during early and late processes of tumor development and progression, we used the BALB/c mouse based WAP-T model, a well characterized immunecompetent mouse model for oncogene-induced mammary carcinogenesis. The clinical relevance of the WAP-T mouse model is emphasized by comparison with human ductal carcinoma in situ [3, 5] and molecular similarities between invasive WAP-T and human triple-negative mammary carcinoma subtypes [6, 7]. These carcinomas represent about 20% of all ductal mammary carcinomas and are characterized by bad prognosis
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