CD47-mediated immune evasion in early-stage lung cancer progression

• Published in: Biochemical and biophysical research communications Vol. 720; p. 150066
• Main Authors: Chuang, Cheng-Hao, Zhen, Yen-Yi, Ma, Juei-Yang, Lee, Tai-Huang, Hung, Huei-Yang, Wu, Chun-Chieh, Wang, Pei-Hui, Huang, Ching-Tang, Huang, Ming-Shyan, Hsiao, Michael, Lee, Ying-Ray, Huang, Chi-Ying F., Chang, Yu-Chan, Yang, Chih-Jen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2024
• Subjects: Animals; antigen presentation; blood serum; carcinogenesis; CD47 Antigen - immunology; CD47 Antigen - metabolism; Cell Line, Tumor; cytoplasm; Disease Progression; Extracellular vesicles; Extracellular Vesicles - immunology; Extracellular Vesicles - metabolism; Female; Humans; Immune checkpoint; Immune Evasion; ligands; lung neoplasms; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Macrophage; macrophages; Macrophages - immunology; Macrophages - metabolism; Mice; neoplasm cells; neoplasm progression; Neoplasm Staging; patients; phagocytosis; transmembrane proteins; Tumor Escape; Tumor microenvironment; Tumor Microenvironment - immunology; xenotransplantation; Extracellular vesicles; Immune checkpoint; Immune evasion; Tumor microenvironment; Macrophage
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150066

Alveolar and interstitial macrophages play crucial roles in eradicating pathogens and transformed cells in the lungs. The immune checkpoint CD47, found on normal and malignant cells, interacts with the SIRPα ligand on macrophages, inhibiting phagocytosis, antigen presentation, and promoting immune evasion. In this study, we demonstrated that CD47 is not only a transmembrane protein, but that it is also highly concentrated in extracellular vesicles from lung cancer cell lines and patient plasma. Abundant CD47 was observed in the cytoplasm of lung cancer cells, aligning with our finding that it was packed into extracellular vesicles for physiological and pathological functions. In our clinical cohort, extracellular vesicle CD47 was significantly higher in the patients with early-stage lung cancer, emphasizing innate immunity inactivation in early tumor progression. To validate our hypothesis, we established an orthotopic xenograft model mimicking lung cancer development, which showed increased serum soluble CD47 and elevated IL-10/TNF-α ratio, indicating an immune-suppressive tumor microenvironment. CD47 expression led to reduced tumor-infiltrating macrophages during progression, while there was a post-xenograft increase in tumor-associated macrophages. In conclusion, CD47 is pivotal in early lung cancer progression, with soluble CD47 emerging as a key pathological effector. •The CD47 immune checkpoint plays a critical role in immune evasion during the early stages of lung cancer.•CD47 exhibits high concentrations in extracellular vesicles, both in vitro and in vivo.•Elevated ratios of serum IL-10 to TNF-α and increased CD47 expression, identified in our orthotopic xenograft animal model, contribute to the promotion of tumor growth.•The interplay with CD47 in vivo is recognized to suppress tumor-infiltrating macrophages while concurrently increasing tumor-associated macrophages.