Wang Denian, Li Sixiang, Yang Zhi, Yu Chunyan, Wu Pengfei, Yang Ying, Zhang Rui, Li Qingyan, Yang Jian, Li Hongchun, Ji Guiyi, Wang Yan, Xie Kang, Liu Yanyan, Wang Kaige, Zhu Daxing, Zhang Wengeng, Liu Dan, Chen Bojiang, Li Weimin
Precision Medicine Research Center, Precision Medicine Key Laboratory of Sichuan Province, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Respiratory and Critical Care Medicine, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Clin Transl Med. 2024 Aug;14(8):e1786. doi: 10.1002/ctm2.1786.
Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune-inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single-cell level.
We performed single-cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co-culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single-cell analyses.
LSCC with COPD showed increased proportions of tumour-associated macrophages (TAMs) and higher levels of CD8 T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74 tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF-CD74 may interact with CD8 T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-programmed cell death-1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion.
Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy.
Our results demonstrated higher proportions of tumour-associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8 T cells in the microenvironment of LSCC with COPD. CD74tumour cells were associated with poor disease prognosis. Migration inhibitory factor (MIF)-CD74 may interact with CD8 T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-PD-L1 signalling pathway, facilitating immune evasion.
慢性阻塞性肺疾病（COPD）与肺癌的发生及预后相关。COPD的存在显著增加了肺鳞状细胞癌（LSCC）的风险。COPD可能通过调节T细胞中免疫抑制因子的表达，在LSCC中促进免疫抑制微环境的形成，但其机制仍不清楚。在本研究中，我们旨在在单细胞水平上解析合并COPD的LSCC的肿瘤微环境特征。
我们对合并或未合并COPD的LSCC肿瘤组织进行了单细胞RNA测序，然后研究了免疫细胞和肿瘤细胞的特征。我们采用了多种技术，包括多光谱成像、流式细胞术、组织芯片分析、生存分析、共培养系统以及体外和体内治疗实验，以验证从单细胞分析中获得的结果。
合并COPD的LSCC显示肿瘤相关巨噬细胞（TAM）比例增加，CD8 T细胞耗竭分子水平升高，这促成了免疫抑制微环境。进一步分析揭示了一群关键的CD74肿瘤细胞，它们同时表达上皮细胞和免疫细胞特征，具有更强的肿瘤发生能力，并预示着更差的总生存期。值得注意的是，合并COPD的LSCC中TAM分泌的迁移抑制因子（MIF）可能促进CD74的激活。MIF-CD74可能与CD8 T细胞相互作用，并通过调节PI3K-STAT3-程序性细胞死亡-1配体1信号通路损害其抗肿瘤活性，促进肿瘤增殖和免疫逃逸。
我们对合并COPD的LSCC肿瘤生态系统的全面描述为相关免疫逃逸机制和免疫治疗潜在靶点提供了更深入的见解。
我们的结果表明，在合并COPD的LSCC微环境中，肿瘤相关巨噬细胞（TAM）比例更高，CD8 T细胞中的耗竭分子水平更高。CD74肿瘤细胞与疾病预后不良相关。迁移抑制因子（MIF）-CD74可能与CD8 T细胞相互作用，并通过调节PI3K-STAT3-PD-L1信号通路损害其抗肿瘤活性，促进免疫逃逸。
