肿瘤细胞治疗研究
英文原题：Integrative multi-omics profiling reveals distinct evolutionary and immunogenic features of brain oligometastasis in lung adenocarcinoma.
我们的发现为寡转移性脑转移瘤的进化轨迹、免疫景观和甲基化模式提供了新的见解，可能为寡转移性脑转移瘤肺癌患者开发创新治疗策略铺平道路。
新出现的证据表明，伴有脑寡转移（oligo-BMs）的肺癌患者可从局部根治性治疗中获益。尽管寡转移性疾病的治疗取得了快速进展，但决定中枢神经系统寡转移表型的分子决定因素仍不明确。
我们对20对配对的原发性肺腺癌和寡转移性脑转移瘤标本进行了1021-panel测序、转录组分析、DNA甲基化定位和多重免疫组织化学，以描绘其演化动态和微环境特征。
原发肿瘤（PTs）与寡转移脑转移瘤（oligo-BMs）之间观察到显著的肿瘤间异质性，而肿瘤内异质性在各病灶间保持保守。亚克隆分析和系统发育重建表明，oligo-BMs表现出以多克隆播散模式为主及平行进展轨迹。此外，与PTs相比，oligo-BMs显示出更为免疫抑制的微环境，其特征为免疫原性细胞死亡信号减弱、免疫激活通路下调以及活化免疫细胞（包括B细胞、NK细胞和Th1细胞）浸润减少。PTs与oligo-BMs在功能基因组区域的甲基化水平高度一致。值得注意的是，我们鉴定出NLGN1作为oligo-BM的潜在调控因子，其基因体区域的高甲基化在机制上与转录上调相关。临床验证显示，与PTs和颅外转移灶相比，NLGN1在BMs中特异性过表达，与晚期病理分期和不良预后相关。体内研究进一步证实NLGN1促进小鼠BM的发生。
BACKGROUND: Emerging evidence has demonstrated that lung cancer patients with brain oligometastases (oligo-BMs) could benefit from local radical therapies. Despite rapid advancements in the treatment of oligometastatic disease, the molecular determinants governing the oligometastatic phenotype in the central nervous system remain elusive. METHODS: We performed 1021-panel sequencing, transcriptome profiling, DNA methylation mapping, and multiplex immunohistochemistry on 20 paired primary lung adenocarcinoma and oligo-BMs specimens to delineate their evolutionary dynamics and microenvironmental characteristics. RESULTS: A pronounced intertumor heterogeneity was observed between primary tumors (PTs) and oligo-BMs, while intratumoral heterogeneity was conserved across lesions. Subclonal analysis and phylogenetic reconstruction demonstrated that oligo-BMs exhibited predominant polyclonal seeding patterns and parallel progression trajectories. Moreover, oligo-BMs displayed a more immunosuppressed microenvironment compared to PTs, characterized by attenuated immunogenic cell death signatures, downregulation of immune-activated pathways, and diminished infiltration of activated immune cells (including B cells, NK cells, and Th1 cells). The methylation levels at functional genomic regions were highly concordant between PTs and oligo-BMs. Notably, we identified NLGN1 as a potential regulator of oligo-BM, where the hypermethylation at its genebody regions was mechanistically associated with transcriptional upregulation. Clinical validation revealed that NLGN1 was specifically overexpressed in BMs compared to PTs and extracranial metastases, correlating with advanced pathological stages and poor prognosis. In vivo studies further confirmed NLGN1 promotes BM in mice. CONCLUSIONS: Our findings provide novel insights into the evolutionary trajectory, immune landscape and methylation pattern of oligo-BMs, potentially paving the way for the development of innovative therapeutic strategies for lung cancer patients with oligo-BMs.
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