Tumor-intrinsic CD74 expression mediates immune evasion in lung cancer with COPD

To better elucidate the complex interaction between COPD and NSCLC, we comprehensively characterized immune cell dynamics and transcriptome profiles of malignant cells in tumor tissues from NSCLC patients with COPD using single-cell RNA sequencing (scRNA-seq). We observed increased fractions of exhausted CD8+ T cells, CCL18+ tumor-associated macrophages (TAMs), and LAMP3+ dendritic cells (DCs) in the immune component of NSCLC with COPD compared with the findings in NSCLC without COPD. Remarkably, a critical cluster of malignant cells from NSCLC with COPD samples, characterized by high expression of CD74, significantly exhibited an epithelial-immune dual signature and was associated with poor prognosis. Interestingly, we found that CD74 facilitated phosphorylation of MAPK/STAT3 to mediate PD-L1 expression and further suppressed CD8+ T cell function, triggering LC progression. Our study provides a comprehensive profiling of the multi-cellular ecosystem of NSCLC with coexisting COPD and reveals that CD74+ cancer cells are potential targets for immunotherapy. Overall design: To systematically elucidate the cellular diversity of NSCLC with or without COPD, we performed scRNA-seq (10X Genomics) of primary tumors from eight patients, including tumors samples (four NSCLC samples without COPD (Tumor) and four NSCLC samples with COPD (CTumor)) and matched adjacent samples (four normal tissues (Normal) and four COPD tissues (COPD))