Abstract P2-05-03: Role of tumor immune environment in tumor initiation and growth rates in mouse mammary tumor models

Autor: Mary L. Disis, Ekram Gadd, Marlese Koehnlein, Piper M. Treuting, Sasha E. Stanton, Lauren Rastetter, Meredith Slota
Rok vydání: 2013
Předmět:
Zdroj: Cancer Research. 73:P2-05
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.sabcs13-p2-05-03
Popis: The role of the tumor immune environment is critical in human breast cancer tumorigenesis and response to therapy: tumors with a Th1 immune activating environment (high cytotoxic CD8+ T cells and low FoxP3 and myeloid derived suppressor cells (MDSC)) show improved response to chemotherapy and improved disease free survival and prognosis, where tumors with a Th2 immune suppressive environment (increased FoxP3, increased MDSC, and decreased CD8 T cells) shows poor response to chemotherapy and worse disease free survival and prognosis. There has not been good correlation with animal models of mammary tumorigenesis and human response to chemotherapy because in mouse models (1) tumor implant models do not show the tumor immune infiltration seen in human tumors (2) xenograph models are not immunocompetent (3) the tumor immune infiltration has not been evaluated the spontaneous mouse mammary models. We evaluated the tumor immune environment in relation to time to tumor development and rate of tumor growth in two commonly used transgenic mouse models: TgMMTV-neu and C3(1)Tag to better define role of the tumor immune environment in tumorigenesis in spontaneous mouse mammary tumor models. Spontaneous tumorigenesis was studied in 80 TgMMTV-neu and 58 C3(1)Tag mice who were observed for tumor development from 6 weeks until tumor ∼1000 mm3. Differences in (1) time to tumor development (2) rate of tumor growth (3) tumor immune environment were evaluated. Between the transgenic mouse models, TgMMTV-neu mice (n = 10) developed tumors later, around 35.0 weeks, and the tumors grew slower with an average growth rate of 47.9 mm3/week than C3(1)Tag mice which developed tumors around 18.2 weeks with an average growth rate of 88.1 (p = 0.006). The tumor infiltration of MDSC inhibitory cells were higher in the C3(1)Tag mice than the TgMMTV-neu mice and approaches significance (17.4% of all lymphocytes in C3(1)Tag and 4.1% in TgMMTV-neu p = 0.08). Furthermore, there are increased CD8+ T cells in TgMMTV-neu mouse tumors than in C3(1)Tag (34.08% CD3+ cells in TgMMTV-neu mice and 22.38% in C3(1)Tag mice, p = 0.07) with similar FoxP3 levels (6.4% in TgMMTV-neu and 10.2% in C3(1)Tag mice p = 0.2) therefore the CD8/FoxP3 ratio in TgMMTV-neu mice is 5.3 where the CD8/FoxP3 ratio in C3(1)Tag mice is 2.2. These data demonstrate that C3(1)Tag mice have more aggressive tumorigenesis than the TgMMTV-neu mice and a more immunosuppressive tumor environment (higher MDSC, lower CD8, and smaller CD8/FoxP3 ratio) supporting the tumor immune environment plays an important role in tumorigenesis. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-03.
Databáze: OpenAIRE
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