Abstract 237: Increased NSCLC tumorigenesis in mice fed a high fat diet is associated with increased plasma IGF-1 levels and PD-1 expression in CD4+ tumor-infiltrating lymphocytes

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.237-237
• Main Authors: Memmott, Regan M., Pearman, Krista, Gills, Joell, Tullot, Tony, Wong, Valerie, Singer, Benjamin, Lastwika, Kristin, D'Alessio, Franco, Dennis, Phillip, Norris, Jeffrey William
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-237

Lung cancer is the leading cause of cancer-related mortality worldwide, and 85% of lung cancer cases are associated with tobacco use. Activating mutations in K-ras have been identified in ~25% of tobacco-associated lung adenocarcinomas. Using mouse models of K-ras-driven lung tumorigenesis, we previously demonstrated that deletion of the IGF-1 gene or reduction of systemic IGF-1 levels using the antidiabetic drug metformin markedly reduced tumor burden. Preclinical and clinical studies suggest that diet composition is the best predictor of IGF-1 levels. Therefore, we hypothesized that diets high in fat or carbohydrate would promote lung tumorigenesis by increasing systemic IGF-1 levels. To assess the effect of diet on systemic IGF-1 levels, 9 week old C57Bl/6J and A/J mice were fed standard cereal, high-carbohydrate, or high-fat (HFD) diets for 12 weeks. Compared to cereal-fed control mice, plasma IGF-1 and insulin levels were increased in both strains of mice fed a HFD, but not in mice fed a diet high in carbohydrate. This was not due to obesity, as only the C57Bl/6J mice fed a HFD had an increase in body weight. We then investigated the effect of HFD on lung tumorigenesis using two mouse models. In the first, C57Bl/6LA2 mice, which harbor a mutation in K-ras, were fed either cereal diet or HFD for 10 weeks following weaning. Lung tumor burden in the mice fed HFD was increased 2.7-fold compared to littermates fed cereal diet. In the second model, the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) was given by intraperitoneal injection to A/J mice beginning at 6 weeks of age. This carcinogen causes lung tumor development by inducing K-ras mutations. After 3 weekly injections of NNK, the mice were randomized to cereal diet or HFD for ten weeks. Mice fed HFD had a 60% increase in lung tumor burden. In both models, there was no relationship between the weight of the mice and lung tumor burden. Immunohistochemical analysis of the proliferation marker Ki-67 showed no significant difference in expression between tumors from mice fed a HFD or a cereal diet. Therefore, we evaluated tumor-infiltrating lymphocytes (TIL) from mice on both diets. Interestingly, both immunohistochemical analysis and flow cytometry demonstrated a 50% reduction in the number of TIL in mice fed HFD compared to mice fed a cereal diet. Additionally, HFD was associated with a 2-fold increase in PD-1+ CD4+ TIL, and the PD-1 staining intensity in these lymphocytes was