PO.MCB09.04 · 分子与细胞生物学
代谢组学分析揭示血浆LPC作为鳞状细胞癌中全身性炎症及免疫治疗应答的指标
Metabolomic profiling reveals plasma LPC as an indicator of systemic inflammation and immunotherapy response in squamous cell carcinoma
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摘要 Abstract
中文摘要
癌症日益被认为是一种全身性疾病，其特征不仅在于局部肿瘤生长，还在于影响疾病进展和治疗应答的广泛代谢和免疫紊乱。为阐明与鳞状细胞癌(SCC)预后及免疫检查点抑制剂(ICI)疗效相关的全身性代谢改变，我们对149例晚期或复发性食管或头颈部SCC患者的血浆进行了整合多组学分析。靶向代谢组学定量了635种代谢物，并将其与详细的临床、蛋白质组学及细胞因子数据集相结合。加权基因相关网络分析揭示，单一代谢物组——溶血磷脂酰胆碱(LPCs)——与格拉斯哥预后评分(全身性炎症和患者生存的标志物)关联最为紧密。在几乎所有可测量的LPC种类中，炎症负荷升高、预后不良的患者血浆水平显著降低。LPC浓度与肿瘤大小、治疗线数或体能状态的相关性极小，表明LPC降低反映的是宿主全身状况而非肿瘤负荷或治疗暴露。生存分析表明，LPC水平低的患者总生存期显著缩短，其中在接受ICI的患者中关联最强。在接受ICI治疗的患者中，尤其是接受一线治疗者，低LPC水平可识别出治疗获益极小的个体，而在从未接受ICI的患者中LPC水平不具预后价值。为探究LPC缺失的生物学背景，我们分析了血浆蛋白质组学和细胞因子谱。低LPC组的蛋白质组学特征揭示了与炎症、固有免疫及凝血激活相关通路的富集；CRP、血清淀粉样蛋白A及其他急性期反应物水平显著升高。细胞因子分析表明，低LPC水平伴随IL-6、IL-10和TNF-alpha升高，进一步支持存在全身性慢性炎症。相反，CCL2和CXCL8等趋化因子在LPC水平保留的患者中更高。综上所述，这些多组学发现表明，LPC降低标志着一种全身性促炎和免疫抑制状态，该状态破坏抗肿瘤免疫并降低对PD-1阻断的应答性。
查看英文原文 English abstract
Cancer is increasingly recognized as a systemic disease characterized not only by local tumor growth but also by widespread metabolic and immunologic disturbances that shape disease progression and treatment response. To clarify systemic metabolic alterations associated with prognosis and immune checkpoint inhibitor (ICI) efficacy in squamous cell carcinoma (SCC), we conducted an integrated multi-omics analysis of plasma from 149 patients with advanced or recurrent esophageal or head and neck SCC. Targeted metabolomics quantified 635 metabolites, which were combined with detailed clinical, proteomic, and cytokine datasets. Weighted gene correlation network analysis revealed a single metabolite group-lysophosphatidylcholines (LPCs)-as most strongly associated with the Glasgow Prognostic Score, a marker of systemic inflammation and patient survival. Across nearly all measurable LPC species, plasma levels were markedly reduced in patients with elevated inflammatory burden and poor prognosis. LPC concentrations showed minimal correlation with tumor size, treatment line, or performance status, indicating that LPC reduction reflects host systemic conditions rather than tumor burden or treatment exposure. Survival analysis demonstrated that patients with low LPC levels had significantly shorter overall survival, with the strongest association observed in those receiving ICIs. Among ICI-treated patients, especially those treated in the first-line setting, low LPC levels identified individuals with minimal therapeutic benefit, whereas LPC levels were not prognostic in patients never exposed to ICIs. To explore the biological context of LPC loss, we analyzed plasma proteomic and cytokine profiles. Proteomic signatures in the low-LPC group revealed enrichment of pathways related to inflammation, innate immunity, and coagulation activation; levels of CRP, serum amyloid A, and other acute-phase reactants were substantially increased. Cytokine profiling demonstrated that low LPC levels were accompanied by elevated IL-6, IL-10, and TNF-alpha, further supporting the presence of systemic chronic inflammation. Conversely, chemokines such as CCL2 and CXCL8 were higher in patients with preserved LPC levels. Together, these multi-omics findings indicate that decreased LPC marks a systemic pro-inflammatory and immunosuppressive state that undermines antitumor immunity and reduces responsiveness to PD-1 blockade.
利益披露 Disclosure
T. Iwasaki, None..
H. Shirota, None..
E. Hishinuma, None..
N. Matsukawa, None..
Y. Kasahara, None.
H. Kawakami,
Eisai Co. Ltd. ).
Bristol-Myers Squibb Co. Ltd. ).
Kobayashi Pharmaceutical. Co., Ltd. ).
Astellas Pharma Inc ).
Taiho Pharmaceutical Co. Ltd ).