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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

Regan M. Memmott, Krista Pearman, Joell Gills, Tony Tullot, Valerie Wong, Benjamin Singer, Kristin Lastwika, Franco D'Alessio, Phillip Dennis and Jeffrey William Norris
Regan M. Memmott
University of Arizona Phoenix, Phoenix, AZ;
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Krista Pearman
Midwestern Univ. - Glendale Campus, Glendale, AZ;
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Joell Gills
Johns Hopkins Medical Institute, Baltimore, MD;
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Tony Tullot
Midwestern Univ. - Glendale Campus, Glendale, AZ;
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Valerie Wong
Midwestern Univ. - Glendale Campus, Glendale, AZ;
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Benjamin Singer
Northwestern University, Evanston, IL;
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Kristin Lastwika
Fred Hutchinson Cancer Research Institute, Seattle, WA;
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Franco D'Alessio
Johns Hopkins University - School of Medicine, Baltimore, MD;
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Phillip Dennis
Astra-Zeneca, MD.
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Jeffrey William Norris
Midwestern Univ. - Glendale Campus, Glendale, AZ;
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DOI: 10.1158/1538-7445.AM2017-237 Published July 2017
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Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

Abstract

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 significantly greater than in mice fed a cereal diet. These results may suggest that a high fat diet increases lung tumorigenesis by increasing systemic IGF-1 levels and by creating an immune-permissive tumor microenvironment.

Citation Format: Regan M. Memmott, Krista Pearman, Joell Gills, Tony Tullot, Valerie Wong, Benjamin Singer, Kristin Lastwika, Franco D'Alessio, Phillip Dennis, Jeffrey William Norris. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 237. doi:10.1158/1538-7445.AM2017-237

  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13 Supplement)
July 2017
Volume 77, Issue 13 Supplement
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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
Regan M. Memmott, Krista Pearman, Joell Gills, Tony Tullot, Valerie Wong, Benjamin Singer, Kristin Lastwika, Franco D'Alessio, Phillip Dennis and Jeffrey William Norris
Cancer Res July 1 2017 (77) (13 Supplement) 237; DOI: 10.1158/1538-7445.AM2017-237

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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
Regan M. Memmott, Krista Pearman, Joell Gills, Tony Tullot, Valerie Wong, Benjamin Singer, Kristin Lastwika, Franco D'Alessio, Phillip Dennis and Jeffrey William Norris
Cancer Res July 1 2017 (77) (13 Supplement) 237; DOI: 10.1158/1538-7445.AM2017-237
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Cancer Research Online ISSN: 1538-7445
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