Multimodal analysis suggests differential immuno-metabolic crosstalk in lung squamous cell carcinoma and adenocarcinoma.
Multimodal analysis suggests differential immuno-metabolic crosstalk in lung squamous cell carcinoma and adenocarcinoma.
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多模式分析提示肺鳞癌和腺癌的免疫代谢串扰差异。
DOI：
10.1038/s41698-021-00248-2
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发表时间：
2022-01-27
影响因子：
7.9
通讯作者：
Perry RJ
中科院分区：
文献类型：
--
作者：
Leitner BP;Givechian KB;Ospanova S;Beisenbayeva A;Politi K;Perry RJ
肿瘤微环境中的免疫代谢是肺癌精确治疗的重要靶点。有趣的是，肥胖使非小细胞肺癌(NSCLC)对免疫检查点抑制的反应得到改善，这表明肺部肿瘤的系统代谢和免疫代谢环境之间存在有趣的关系。我们假设内脏脂肪和18F-脱氧葡萄糖摄取影响肿瘤免疫代谢环境，这种双向关系在非小细胞肺癌亚型、肺腺癌(LUAD)和肺鳞癌(LUSC)中不同。通过结合18F-FDG PET/CT成像、批量和单细胞RNA测序以及组织学，我们观察到LUSC比LUAD对葡萄糖的依赖程度更高。在高葡萄糖摄取的LUAD肿瘤中，谷氨酰胺酶表达下调，提示葡萄糖和谷氨酰胺代谢之间存在权衡；而在高葡萄糖摄取的LUSC肿瘤中，与脂肪酸和氨基酸代谢相关的基因也增加。我们发现肿瘤浸润性T细胞在NSCLC中谷氨酰胺酶、核糖体蛋白37和胱硫氨酸伽马裂解酶的表达最高，这突出了该细胞类型的代谢灵活性。进一步，我们证明内脏肥胖，而不是体重指数(BMI)，与LUAD的肿瘤葡萄糖摄取呈正相关，高BMI的患者具有良好的预后转录谱，而高内脏脂肪患者的肿瘤的预后基因表达较差。我们假设，由于LUAD的代谢灵活性，代谢辅助治疗在LUSC可能比LUAD更成功，在开发治疗NSCLC的精确医学方法时，应该考虑内脏肥胖，而不仅仅是BMI。
Immunometabolism within the tumor microenvironment is an appealing target for precision therapy approaches in lung cancer. Interestingly, obesity confers an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC), suggesting intriguing relationships between systemic metabolism and the immunometabolic environment in lung tumors. We hypothesized that visceral fat and 18F-Fluorodeoxyglucose uptake influenced the tumor immunometabolic environment and that these bidirectional relationships differ in NSCLC subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). By integrating 18F-FDG PET/CT imaging, bulk and single-cell RNA-sequencing, and histology, we observed that LUSC had a greater dependence on glucose than LUAD. In LUAD tumors with high glucose uptake, glutaminase was downregulated, suggesting a tradeoff between glucose and glutamine metabolism, while in LUSC tumors with high glucose uptake, genes related to fatty acid and amino acid metabolism were also increased. We found that tumor-infiltrating T cells had the highest expression of glutaminase, ribosomal protein 37, and cystathionine gamma-lyase in NSCLC, highlighting the metabolic flexibility of this cell type. Further, we demonstrate that visceral adiposity, but not body mass index (BMI), was positively associated with tumor glucose uptake in LUAD and that patients with high BMI had favorable prognostic transcriptional profiles, while tumors of patients with high visceral fat had poor prognostic gene expression. We posit that metabolic adjunct therapy may be more successful in LUSC rather than LUAD due to LUAD’s metabolic flexibility and that visceral adiposity, not BMI alone, should be considered when developing precision medicine approaches for the treatment of NSCLC.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
10.9
作者：
Cortellini A;Ricciuti B;Tiseo M;Bria E;Banna GL;Aerts JG;Barbieri F;Giusti R;Cortinovis DL;Migliorino MR;Catino A;Passiglia F;Torniai M;Morabito A;Genova C;Mazzoni F;Di Noia V;Signorelli D;Gelibter A;Occhipinti MA;Rastelli F;Chiari R;Rocco D;Inno A;De Tursi M;Di Marino P;Mansueto G;Zoratto F;Grossi F;Filetti M;Pizzutilo P;Russano M;Citarella F;Cantini L;Targato G;Nigro O;Ferrara MG;Buti S;Scodes S;Landi L;Guaitoli G;Della Gravara L;Tabbò F;Ricciardi S;De Toma A;Friedlaender A;Petrelli F;Addeo A;Porzio G;Ficorella C
通讯作者：
Ficorella C
影响因子：
3.4
作者：
Calling, Susanna;Hedblad, Bo;Janzon, Lars
通讯作者：
Janzon, Lars
影响因子：
5.8
作者：
Abildgaard, Julie;Danielsen, Else Rubaek;Lindegaard, Birgitte
通讯作者：
Lindegaard, Birgitte
影响因子：
4.7
作者：
Ardesch FH;Ruiter R;Mulder M;Lahousse L;Stricker BHC;Kiefte-de Jong JC
通讯作者：
Kiefte-de Jong JC