慢性阻塞性肺疾病（COPD）影响肺癌的发病率和预后。 COPD 的存在会显着增加患肺鳞状细胞癌 (LSCC) 的风险。 COPD 可能通过调节 T 细胞中免疫抑制因子的表达来促进 LSCC 的免疫抑制微环境，但其机制仍不清楚。在本研究中，我们的目的是在单细胞水平上破译患有慢性阻塞性肺病的喉鳞癌的肿瘤微环境特征。我们对患有或不患有慢性阻塞性肺病的喉鳞癌的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、组织微阵列分析、生存分析、共培养系统以及体外和体内治疗实验，来验证从单细胞分析中获得的结果。患有 COPD 的 LSCC 显示，肿瘤相关巨噬细胞 (TAM) 和较高水平的 CD8 T 细胞耗竭分子，这有助于形成免疫抑制微环境。进一步的分析揭示了一个关键的 CD74 肿瘤细胞簇，它们表达上皮细胞和免疫细胞特征，表现出更强的肿瘤发生能力，并预测总体生存率较差。值得注意的是，患有 COPD 的 LSCC 的 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，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避。我们对 LSCC 肿瘤生态系统的全面了解COPD 为相关免疫逃避机制和免疫治疗的潜在靶点提供了更深入的见解。我们的结果表明，在患有 COPD 的 LSCC 微环境中，肿瘤相关巨噬细胞 (TAM) 的比例较高，CD8 T 细胞中的耗竭分子水平较高。 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，促进免疫逃避。© 2024 作者。约翰·威利出版的《临床与转化医学》

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. CD74+tumour 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.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.