Gu Zhan, Heng Yongqing, Fan Rui, Luo Jie, Ju Lixia
Department of Integrative Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Cancer Cell Int. 2025 Apr 21;25(1):157. doi: 10.1186/s12935-025-03785-z.
Despite its rapid growth and early metastasis, small cell lung cancer (SCLC) is more chemosensitive than other lung cancers. However, some patients with extensive-stage SCLC (ES-SCLC) do not respond to first-line chemotherapy, resulting in poorer prognoses due to inter- and intratumoral heterogeneity. In this study, we conducted single-cell RNA sequencing of 9 treatment-naive ES-SCLC samples. Based on comprehensive imaging evidence collected before and after two cycles of first-line chemotherapy and sample types, the 9 samples were categorized into three groups: progressive disease with the pleural effusion sample (PD_PE group, n = 1), progressive disease with the primary tumor samples (PD_TU group, n = 2), and partial response with the primary tumor samples (PR_TU group, n = 6). Based on transcriptomic landscape and cell type composition, the PD samples represent a multicellular ecosystem distinct from PR samples. The immune response, along with the elevated expression of immune-related genes such as LTF, SLPI, SPARC and IGLV1-51, might correlate with a poor first-line chemotherapy response in ES-SCLC. We also observed that T cells, particularly effector T cells, were more abundant in PD_TU group, with TNFA signaling via NFκB being significantly enriched. The PD_TU group was strongly enriched with macrophages and tumor-associated macrophages (TAMs), and angiogenesis in TAMs was highly enriched. Immunomodulatory fibroblasts were highly abundant in PD_TU group, and the pathways of epithelial-mesenchymal transition and angiogenesis were upregulated. This study offers the first comprehensive insights into the cellular and molecular heterogeneity in treatment-naive patients with ES-SCLC with different chemotherapy responses.
尽管小细胞肺癌（SCLC）生长迅速且早期转移，但它比其他肺癌对化疗更敏感。然而，一些广泛期小细胞肺癌（ES-SCLC）患者对一线化疗无反应，由于肿瘤间和肿瘤内的异质性，导致预后较差。在本研究中，我们对9例未经治疗的ES-SCLC样本进行了单细胞RNA测序。根据一线化疗两个周期前后收集的综合影像证据和样本类型，将9个样本分为三组：伴有胸腔积液样本的疾病进展组（PD_PE组，n = 1）、伴有原发肿瘤样本的疾病进展组（PD_TU组，n = 2）和伴有原发肿瘤样本的部分缓解组（PR_TU组，n = 6）。基于转录组图谱和细胞类型组成，疾病进展样本代表了一个与部分缓解样本不同的多细胞生态系统。免疫反应以及LTF、SLPI、SPARC和IGLV1-51等免疫相关基因表达的升高，可能与ES-SCLC一线化疗反应不佳相关。我们还观察到，T细胞，尤其是效应T细胞，在PD_TU组中更为丰富，通过NFκB的肿瘤坏死因子α信号通路显著富集。PD_TU组巨噬细胞和肿瘤相关巨噬细胞（TAM）大量富集，TAM中的血管生成高度富集。免疫调节性成纤维细胞在PD_TU组中高度丰富，上皮-间质转化和血管生成途径上调。本研究首次全面深入了解了未经治疗的不同化疗反应的ES-SCLC患者的细胞和分子异质性。
