Gähler Alexander, Trufa Denis I, Chiriac Mircea T, Tausche Patrick, Hohenberger Katja, Brunst Ann-Kathrin, Rauh Manfred, Geppert Carol I, Rieker Ralf J, Krammer Susanne, Leberle Anna, Neurath Markus F, Sirbu Horia, Hartmann Arndt, Finotto Susetta
Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Thoracic Surgery, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
Front Oncol. 2022 Apr 29;12:873293. doi: 10.3389/fonc.2022.873293. eCollection 2022.
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.
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.
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.
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 . 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.
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.
肺癌是西方国家第二常见的癌症类型，死亡率很高。在肿瘤的发生和发展过程中，其周围环境中的营养物质起着核心作用。肿瘤细胞严重依赖葡萄糖代谢和摄取。肿瘤细胞代谢以瓦伯格效应为主导，即在有氧条件下肿瘤细胞从丙酮酸产生大量乳酸。因此，我们推测，减少饮食中的碳水化合物可能有助于增强当前免疫疗法的抗肿瘤作用，并额外靶向肿瘤免疫逃逸。
减少碳水化合物以改善当前免疫疗法之间的联系尚不清楚。因此，我们旨在分析不同葡萄糖水平对肿瘤发生、发展和抗肿瘤免疫反应的影响。
我们将肺腺癌队列的临床参数与不同的代谢标志物进行关联。此外，我们在不同葡萄糖水平下对A549肿瘤细胞系进行了细胞培养实验。最后，我们在实验性肺癌小鼠模型中研究了低碳水化合物和高碳水化合物饮食对肿瘤进展和不同免疫亚群的影响。
我们发现，肺腺癌（LUAD）患者的体重指数（BMI）、血糖水平、总生存期（OS）降低与肺肿瘤区域胰岛素样生长因子-1受体（IGF1R）的表达之间存在正相关。此外，细胞外葡萄糖增加诱导A549 LUAD细胞中IGF1R表达。在LUAD小鼠模型中的功能研究表明，葡萄糖限制饮食导致肿瘤负荷降低。这一发现与肺浸润性细胞毒性CD8 + T效应记忆（TEM）、组织驻留记忆T（TRM）和自然杀伤细胞的增加以及IGFR mRNA表达降低有关，表明葡萄糖限制调节肿瘤微环境中的肺免疫。
这些结果表明，葡萄糖限制饮食可改善宿主的肺免疫反应，并抑制实验性肺腺癌中的肿瘤生长。由于LUAD患者的葡萄糖水平与术后生存率呈负相关，葡萄糖限制饮食成为LUAD患者的一种治疗途径。
