Cui Xiaolu, Liu Siyuan, Song He, Xu Jingjing, Sun Yanbin
Department of Urology, First Hospital of China Medical University, Shenyang, Liaoning Province, 110001, China.
Department of Thoracic Surgery, First Hospital of China Medical University, Shenyang, Liaoning Province, 110001, China.
Mol Cancer. 2025 Apr 9;24(1):111. doi: 10.1186/s12943-025-02287-w.
Non-small cell lung cancer (NSCLC) represents the most common pathological type of lung cancer, and the combination of neoadjuvant immunotherapy with chemotherapy has emerged as the first-line treatment for NSCLC. Nevertheless, the efficacy of this therapeutic approach remains variable. The present study aims to examine the impact of chemoimmunotherapy in NSCLC patients, with a view to identifying key molecules, critical cell subpopulations, communication patterns and spatial distributions that potentially correlate with therapeutic sensitivity. A total of 16 lung cancer tissue samples were collected from a cohort of 12 NSCLC patients and subjected to single-cell RNA and spatial transcriptome sequencing. Our data demonstrated that the distribution of CD4 + Treg T cells and mCAFs indicated an immunosuppressive tumor microenvironment, while the accumulation of CD4 + Th17 T cells and iCAFs could act as a positive marker for the sensitivity to chemoimmunotherapy. Furthermore, a significant high level of SELENOP-macrophages was observed in tissues from positive responders, and a strong co-localization between SELENOP-macrophages and antigen-presenting cancer associated fibroblasts (CAFs) in the tumor boundaries was identified, indicating the cooperative roles of these two cell types in response to combined therapy. Moreover, SELENOP-macrophages were observed to be accumulated in tertiary lymphoid structures, which further suggested its critical role in recruiting lymphocytes. Furthermore, analysis of cell-cell communication, based on spatial transcriptomics, suggests that the interactions between SELENOP-macrophages, apCAFs, CD4 + and CD8 + T cells were significantly enhanced in responders. In addition, SELENOP-macrophages recruited CD4 + Naïve, Helper and CD8 + Naïve T cells through pathways such as the cholesterol, interleukin, chemokine and HLA when responding to combined therapy. The present study further unveils the dynamic spatial and transcriptional changes in the tumor microenvironment of non-small cell lung cancer in response to combination therapy.
非小细胞肺癌（NSCLC）是最常见的肺癌病理类型，新辅助免疫疗法与化疗联合已成为NSCLC的一线治疗方案。然而，这种治疗方法的疗效仍存在差异。本研究旨在探讨化疗免疫疗法对NSCLC患者的影响，以确定可能与治疗敏感性相关的关键分子、关键细胞亚群、通讯模式和空间分布。从12例NSCLC患者队列中收集了16个肺癌组织样本，并进行了单细胞RNA和空间转录组测序。我们的数据表明，CD4+调节性T细胞（Treg T细胞）和基质相关成纤维细胞（mCAFs）的分布表明肿瘤微环境具有免疫抑制作用，而CD4+辅助性T细胞17（Th17 T细胞）和炎性相关成纤维细胞（iCAFs）的积累可作为化疗免疫疗法敏感性的阳性标志物。此外，在阳性反应者的组织中观察到硒蛋白P（SELENOP）+巨噬细胞水平显著升高，并且在肿瘤边界处SELENOP+巨噬细胞与抗原呈递性癌症相关成纤维细胞（CAFs）之间存在强烈的共定位，表明这两种细胞类型在联合治疗反应中发挥协同作用。此外，观察到SELENOP+巨噬细胞在三级淋巴结构中积累，这进一步表明其在招募淋巴细胞中的关键作用。此外，基于空间转录组学的细胞间通讯分析表明，在反应者中SELENOP+巨噬细胞、活化的CAFs（apCAFs）、CD4+和CD8+T细胞之间的相互作用显著增强。此外，在对联合治疗作出反应时，SELENOP+巨噬细胞通过胆固醇、白细胞介素、趋化因子和人类白细胞抗原等途径招募CD4+初始T细胞、辅助性T细胞和CD8+初始T细胞。本研究进一步揭示了非小细胞肺癌肿瘤微环境在联合治疗反应中的动态空间和转录变化。
