Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma.

Autor:	Gähler A; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Trufa DI; Department of Thoracic Surgery, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Chiriac MT; Department of Medicine 1 - Gastroenterology, Pneumology and Endocrinology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Tausche P; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Hohenberger K; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Brunst AK; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Rauh M; Department of Paediatrics and Adolescent Medicine, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Geppert CI; Institute of Pathology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Rieker RJ; Institute of Pathology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Krammer S; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Leberle A; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany., Neurath MF; Department of Medicine 1 - Gastroenterology, Pneumology and Endocrinology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Sirbu H; Department of Thoracic Surgery, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Hartmann A; Institute of Pathology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Finotto S; Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Apr 29; Vol. 12, pp. 873293. Date of Electronic Publication: 2022 Apr 29 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.873293
Abstrakt:	Background: Lung cancer is the second common cancer type in western countries and has a high mortality. During the development and progression of the tumor, the nutrients in its environment play a central role. The tumor cells depend crucially on glucose metabolism and uptake. Tumor cell metabolism is dominated by the Warburg effect, where tumor cells produce large amounts of lactate from pyruvate under aerobic conditions. We thus reasoned that, reducing carbohydrates in the diet might support anti-tumoral effects of current immunotherapy and additionally target tumor immune escape. Objectives: The link between reducing carbohydrates to improve current immunotherapy is not clear. We thus aimed at analyzing the effects of different glucose levels on the tumor development, progression and the anti-tumoral immune response. Methods: We correlated the clinical parameters of our LUAD cohort with different metabolic markers. Additionally, we performed cell culture experiments with A549 tumor cell line under different glucose levels. Lastly, we investigated the effect of low and high carbohydrate diet in an experimental murine model of lung cancer on the tumor progression and different immune subsets. Results: Here we found a positive correlation between the body mass index (BMI), blood glucose levels, reduced overall survival (OS) and the expression of Insulin-like growth factor-1 receptor (IGF1R) in the lung tumoral region of patients with lung adenocarcinoma (LUAD). Furthermore, increasing extracellular glucose induced IGF1R expression in A549 LUAD cells. Functional studies in a murine model of LUAD demonstrated that, glucose restricted diet resulted in decreased tumor load in vivo . This finding was associated with increased presence of lung infiltrating cytotoxic CD8+ T effector memory (TEM), tissue resident memory T (TRM) and natural killer cells as well as reduced IGFR mRNA expression, suggesting that glucose restriction regulates lung immunity in the tumor microenvironment. Conclusions: These results indicate that, glucose restricted diet improves lung immune responses of the host and suppresses tumor growth in experimental lung adenocarcinoma. As glucose levels in LUAD patients were negatively correlated to postoperative survival rates, glucose-restricted diet emerges as therapeutic avenue for patients with LUAD. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Gähler, Trufa, Chiriac, Tausche, Hohenberger, Brunst, Rauh, Geppert, Rieker, Krammer, Leberle, Neurath, Sirbu, Hartmann and Finotto.)
Databáze:	MEDLINE
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