Dong Huixing, Hu Feng, Hao Bo, Jin Xiaoyan, Zheng Qi, Su Yiliang
Department of Pulmonary and Critical Care Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai, 200336, China.
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.
Eur Geriatr Med. 2024 Oct;15(5):1509-1522. doi: 10.1007/s41999-024-01032-8. Epub 2024 Sep 8.
The immune profiles of elder patients with non-small cell lung cancer (NSCLC) differ significantly from those of younger patients. The tumor microenvironment (TME) is a crucial factor in cancer progression and therapeutic responses. The present study aims to decipher the difference in TME between younger and elderly patients with lung cancers.
We downloaded single-cell RNA data from public databases. The algorithm of uniform manifold approximation and projection (UMAP) was applied to cluster and visualize single-cell sequencing data. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) analysis were performed to evaluate the physiological functional characteristics in sub-group cells. CellPhoneDB was used to identify cell-cell interactions between immune cells within TME.
We conducted single-cell RNA sequencing on 96,491 cells from elderly patients and 169,207 cells from younger patients, respectively. We observed that epithelial cells were the predominant component of the TME in younger patients, whereas T/NK cells were the predominant cell type in the TME of elderly patients. We also found that there was a higher proportion of Tregs and a lower proportion of NK, effector CD8T and γδT cells in elder patients compared with younger patients. In addition, a comparative GSEA analysis of NK cells between older and younger patients revealed that the pathways of Parkinson's disease, Alzheimer's disease, mismatch repair, and base excision repair were up-regulated in NK cells from elderly patients, while the pathways related to natural killer cell-mediated cytotoxicity and allograft rejection were downregulated. Furthermore, we identified tumor-associated neutrophils (TANs) in elder patients, and GSVA analysis demonstrated that the pathway of angiogenesis was upregulated, and the pathway of interferon_γ_response, inflammatory_response, TNFα_signaling_via_NFκB pathways were downregulated. Importantly, the pro-inflammatory response scores of complement C1q C chain positive (C1QC) macrophages, tissue-resident macrophages (TRM), non-classical monocytes (NCM), secreted phosphoprotein 1 positive (SPP1) macrophages, and classical monocytes (CM) in elder patients were significantly lower compared to those in younger patients. Finally, cell-to-cell communication analyses unveiled the disparities in regulatory patterns between elder and younger patients, namely the pairs of CXCL13-ACKR4 and CSF1-SIRPA in elder patients and the pairs of CTLA4-CD86 and TIGIT-NECTIN2 in younger patients.
This study reveals the distinct immune profiles between younger and elder NSCLC patients, and the elder patients were likely to exhibit a more immunosuppressive TME and attenuated tumor-killing capability compared with younger patients.
老年非小细胞肺癌（NSCLC）患者的免疫谱与年轻患者有显著差异。肿瘤微环境（TME）是癌症进展和治疗反应的关键因素。本研究旨在解读年轻和老年肺癌患者TME的差异。
我们从公共数据库下载了单细胞RNA数据。应用均匀流形近似和投影（UMAP）算法对单细胞测序数据进行聚类和可视化。进行基因集变异分析（GSVA）和基因集富集分析（GSEA）以评估亚组细胞中的生理功能特征。使用CellPhoneDB识别TME内免疫细胞之间的细胞间相互作用。
我们分别对老年患者的96491个细胞和年轻患者的169207个细胞进行了单细胞RNA测序。我们观察到，上皮细胞是年轻患者TME的主要成分，而T/NK细胞是老年患者TME中的主要细胞类型。我们还发现，与年轻患者相比，老年患者中调节性T细胞（Tregs）比例更高，自然杀伤细胞（NK）、效应性CD8T细胞和γδT细胞比例更低。此外，对老年和年轻患者的NK细胞进行的比较GSEA分析显示，帕金森病、阿尔茨海默病、错配修复和碱基切除修复途径在老年患者的NK细胞中上调，而与自然杀伤细胞介导的细胞毒性和同种异体移植排斥相关的途径下调。此外，我们在老年患者中鉴定出肿瘤相关中性粒细胞（TANs），GSVA分析表明血管生成途径上调，干扰素γ反应、炎症反应、TNFα通过NFκB信号通路下调。重要的是，老年患者中补体C1q C链阳性（C1QC）巨噬细胞、组织驻留巨噬细胞（TRM）、非经典单核细胞（NCM）、分泌性磷蛋白1阳性（SPP1）巨噬细胞和经典单核细胞（CM）的促炎反应评分明显低于年轻患者。最后，细胞间通讯分析揭示了老年和年轻患者之间调节模式的差异，即老年患者中的CXCL13-ACKR4和CSF1-SIRPA对以及年轻患者中的CTLA4-CD86和TIGIT-NECTIN2对。
本研究揭示了年轻和老年NSCLC患者之间不同的免疫谱，与年轻患者相比，老年患者可能表现出更强的免疫抑制性TME和减弱的肿瘤杀伤能力。
