Optical imaging of labeled cells is the most prevailing method for cell tracking in mouse models. However, the immunogenicity of xenobiotic reporter genes, such as the commonly used firefly luciferase (ffLuc) and enhanced green fluorescence protein (eGFP), results in inconsistency in cell labeling and tumor progression, preventing their use in host mice with normal immunity. To resolve this issue, we have generated a reporter gene-tolerized transgenic mouse in which an ffLuc-eGFP fusion gene was targeted to the anterior pituitary gland using a rat Growth Hormone promoter (dubbed the “glowing-head” mouse). When ffLuc-eGFP-labeled Lewis Lung Carcinoma (LLC) tissue was subcutaneously transplanted into syngeneic glowing-head mice (GH-c-brd), their non-transgenic litter-mates (WT-c-brd), and immunocompromised Nod-Scid (balb/c) mice, anti-GFP antibody was induced only in the circulation of WT-c-brd. Labeled LLC also exhibited fewer CD4+ T cells but more macrophages in GH-c-brd than in WT-c-brd, suggesting it induced adaptive immunity in the latter. Moreover, GH-c-brd exhibited faster subcutaneous tumor growth and post-resection metastatic progression, and maintained more consistent tumor labeling, as compared to WT-c-brd and even Nod-Scid mice. Interestingly, in an adjuvant chemotherapeutic setting, the immunogenicity of the labeled tumor was able to deter metastatic progression in a manner similar to that obtained by drug treatment. We conclude that the immunogenicity of xenobiotic labeling markers can significantly influence disease progression and therapeutic responses thereby compromising immunocompetent preclinical cancer models, and that the glowing-head mouse can be used to circumvent such problems and promote consistent disease monitoring.

Citation Format: Chi-Ping Day, Zoe Weaver, John Carter, Carrie Bonomi, Terry Van Dyke, Melinda Hollingshead, Glenn Merlino. Immunological naturalization of immunocompetent host mice to luciferase-GFP for consistent tracking of transplanted tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1556. doi:10.1158/1538-7445.AM2013-1556