PO.PS01.01 · 人群科学
体重指数相关的转录组特征揭示非小细胞肺癌中免疫、基质和代谢重塑：对肥胖悖论的见解
Body mass index-associated transcriptomic signatures reveal immune, stromal, and metabolic rewiring in non-small cell lung cancer: Insights into the obesity paradox
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摘要 Abstract
中文摘要
尽管肥胖会增加癌症风险，但肥胖的非小细胞肺癌（NSCLC）患者却矛盾地表现出更好的生存。这种“肥胖悖论”的生物学基础仍不清楚。高通量分析可揭示与体重指数（BMI）相关的转录网络，这些网络塑造免疫、代谢和基质反应，从而阐明这种“肥胖悖论”是否反映了真正的肿瘤-微环境相互作用，而非临床混杂因素。我们分析了俄亥俄州立大学 ORIEN Avatar 数据中 263 例 NSCLC 患者的全转录组样本。患者被分为消瘦组（BMI<25；n=93）、超重组（25≤BMI<30；n=78）和肥胖组（BMI≥30；n=92）。在所有组间进行差异表达（DE）分析（消瘦对超重、消瘦对肥胖、超重对肥胖）。保留显著失调的转录本（p<0.01 且 |倍数变化|>1.5）用于下游分析。采用 Ingenuity Pathway Analysis（p<0.05）进行经典通路富集。出现了不同的 BMI 依赖性转录组特征。在肥胖对消瘦中，40 个转录本失调并富集于代谢过程（NAD⁺ 生物合成、非氧化 PPP），提示代谢重编程。超重对消瘦揭示了 358 个失调转录本，伴随免疫激活上调（Th1/Th2、ICOS-ICOSL、IL-2 家族、B 细胞中的 PI3K 信号），表明适应性免疫尤其是 T 细胞免疫增强。肥胖对超重揭示了 304 个失调转录本，富集于细胞外基质、血小板-胶原和破骨细胞信号，提示肥胖中基质重塑受到抑制。失调转录本的重叠较小（O对L∩O对Ow=1；O对L∩Ow对L=7；O对Ow∩Ow对L=52；三者重叠≈0），提示各组特异性生物学。我们的研究结果描绘了 NSCLC 中三种 BMI 相关的程序：超重肿瘤中的免疫激活、肥胖中的 ECM 抑制和血小板信号，以及肥胖对消瘦肿瘤中的代谢重塑。中度肥胖似乎促成了免疫活跃的微环境，而更高的肥胖度则诱导基质静止和氧化还原适应，这与更高 BMI 下免疫治疗结局改善的报道相一致。肥胖亚组的 ECM/血小板和 NAD⁺ 补救/PPP 特征提示可采用联合策略（例如，基质或抗血小板药物联合 PD-1/PD-L1 阻断、NAMPT 抑制），并提示 BMI 相关的分子异质性可能促成了“肥胖悖论”。
查看英文原文 English abstract
Although obesity increases cancer risk, obese patients with non-small cell lung cancer (NSCLC) paradoxically exhibit better survival. The biological basis of this “ obesity paradox ” remains unclear. High-throughput profiling can reveal body mass index (BMI)-linked transcriptional networks that shape immune, metabolic, and stromal responses, clarifying whether this “obesity paradox” reflects true tumor-microenvironment interactions rather than clinical confounders.We analyzed whole-transcriptome samples from 263 NSCLC patients in the ORIEN Avatar data at The Ohio State University. Patients were stratified into Lean (BMI<25; n=93), Overweight (25≤BMI<30; n=78), and Obese (BMI≥30; n=92) groups. Differential expression (DE) analyses (Lean vs Overweight, Lean vs Obese, Overweight vs Obese) were performed across all groups. Significantly deregulated transcripts (p<0.01 and |fold-change|>1.5) were retained for downstream analyses. Canonical pathway enrichment was conducted using Ingenuity Pathway Analysis (p<0.05).Distinct BMI-dependent transcriptomic signatures emerged. In Obese vs Lean, 40 transcripts were deregulated and enriched for metabolic processes (NAD⁺ biosynthesis, non-oxidative PPP), suggesting metabolic reprogramming. Overweight vs Lean revealed 358 deregulated transcripts with upregulated immune activation (Th1/Th2, ICOS-ICOSL, IL-2 family, PI3K signaling in B cells), indicating enhanced adaptive, particularly T-cell, immunity. Obese vs Overweight revealed 304 deregulated transcripts enriched for extracellular matrix, platelet-collagen, and osteoclast signaling, implying stromal remodeling suppression in obesity. Overlap of deregulated transcripts was modest (OvsL∩OvsOw=1; OvsL∩OwvsL=7; OvsOw∩OwvsL=52; triple overlap≈0), implying group-specific biology.Our findings delineate three BMI-linked programs in NSCLC: immune activation in overweight tumors, ECM suppression and platelet signaling in obesity, and metabolic rewiring in obese versus lean tumors. Moderate adiposity appears to foster an immune-active microenvironment, whereas higher adiposity induces stromal quiescence and redox adaptation, consistent with reports of improved immunotherapy outcomes at higher BMI. The obese subgroup's ECM/platelet and NAD⁺ salvage/PPP signatures nominate combinatorial strategies (e.g., stromal or antiplatelet agents with PD-1/PD-L1 blockade, NAMPT inhibition) and suggest that BMI-associated molecular heterogeneity may contribute to the “obesity paradox.”
利益披露 Disclosure
R. Borea, None..
E. Shankar, None..
F. Drago, None..
C. Ayala de Miguel, None..
E. Puchulu-Campanella, None..
C. Rolfo, None..
G. Nigita, None.