CD14 APOE 细胞和 MMP7 肿瘤细胞的共存导致非小细胞肺癌免疫治疗反应较差。
The co-location of CD14+APOE+ cells and MMP7+ tumour cells contributed to worse immunotherapy response in non-small cell lung cancer.
发表日期:2024 Sep
作者:
Guangyu Fan, Tongji Xie, Le Tang, Lin Li, Xiaohong Han, Yuankai Shi
来源:
Clinical and Translational Medicine
摘要:
肿瘤内免疫浸润是影响非小细胞肺癌(NSCLC)免疫治疗反应的关键决定因素。然而,其表型和相关的空间结构仍然难以捉摸。为了克服这些限制,我们进行了一项全面的研究,其中包括空间转录组 (ST) 数据(来自 6 个样本的 28,712 个点)。我们确定了两种不同的肿瘤内浸润模式:免疫排斥(以骨髓细胞为特征)和免疫激活(以浆细胞为特征)。免疫排斥和免疫激活特征分别对 NSCLC 患者的生存产生不利和有利的作用。值得注意的是,CD14 APOE细胞被认为是免疫排除样本中的主要细胞类型,其上皮-间质转化增加,免疫活性降低。在 ST 和批量转录组数据中观察到 CD14 APOE 细胞和 MMP7 肿瘤细胞的共定位,并通过对 20 个 NSCLC 样本进行的多重免疫荧光进行验证。共定位区域表现出增殖相关途径和缺氧活动的上调。这种共定位抑制了 T 细胞浸润和三级淋巴结构的形成。 CD14 APOE 细胞和 MMP7 肿瘤细胞均与较差的存活率相关。在 ORIENT-3 临床试验的免疫治疗队列中,反应不佳的 NSCLC 患者表现出较高的 CD14 APOE 细胞和 MMP7 肿瘤细胞浸润。在共定位区域内,MK、SEMA3 和巨噬细胞迁移抑制因子 (MIF) 信号通路在细胞间通讯中最活跃。这项研究确定了 NSCLC 中的免疫排斥和激活模式以及 CD14 APOE 细胞和 MMP7 肿瘤细胞的共置是免疫抵抗的贡献者。© 2024 作者。约翰·威利出版的《临床与转化医学》
Intra-tumour immune infiltration is a crucial determinant affecting immunotherapy response in non-small cell lung cancer (NSCLC). However, its phenotype and related spatial structure have remained elusive. To overcome these restrictions, we undertook a comprehensive study comprising spatial transcriptomic (ST) data (28 712 spots from six samples). We identified two distinct intra-tumour infiltration patterns: immune exclusion (characterised by myeloid cells) and immune activation (characterised by plasma cells). The immune exclusion and immune activation signatures showed adverse and favourable roles in NSCLC patients' survival, respectively. Notably, CD14+APOE+ cells were recognised as the main cell type in immune exclusion samples, with increased epithelial‒mesenchymal transition and decreased immune activities. The co-location of CD14+APOE+ cells and MMP7+ tumour cells was observed in both ST and bulk transcriptomics data, validated by multiplex immunofluorescence performed on 20 NSCLC samples. The co-location area exhibited the upregulation of proliferation-related pathways and hypoxia activities. This co-localisation inhibited T-cell infiltration and the formation of tertiary lymphoid structures. Both CD14+APOE+ cells and MMP7+ tumour cells were associated with worse survival. In an immunotherapy cohort from the ORIENT-3 clinical trial, NSCLC patients who responded unfavourably exhibited higher infiltration of CD14+APOE+ cells and MMP7+ tumour cells. Within the co-location area, the MK, SEMA3 and Macrophage migration inhibitory factor (MIF) signalling pathway was most active in cell‒cell communication. This study identified immune exclusion and activation patterns in NSCLC and the co-location of CD14+APOE+ cells and MMP7+ tumour cells as contributors to immune resistance.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.