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Expression of CD47 and SIRPα Macrophage Immune-Checkpoint Pathway in Non-Small-Cell Lung Cancer
Alexandra Giatromanolaki1, Achilleas Mitrakas1, Ioannis Anestopoulos1,2,3
1Department of Pathology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
Background:
Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRPα ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development.
Methods:
We investigated the expression of CD47/SIRPα molecules in a series of 98 NSCLCs, in parallel with the infiltration of tumor stroma by CD68+ macrophages, tumor-infiltrating lymphocytes (TILs), and PD-L1/PD-1 molecules.
Results:
Extensive membranous CD47 expression by cancer cells characterized 29/98 cases. SIRPα and CD68 were expressed, to a varying extent, by tumor-associated macrophages (Μφ, TAMs). A high CD68Mφ-score in inner tumor areas was linked with improved overall survival (p = 0.005); and this was independent of the stage (p = 0.02, hazard ratio 0.4). In contrast, high SIRPα expression by CD68+ TAMs (SIRPα/CD68-ratio) was linked with CD47 expression by cancer cells, low TIL-score, and poor prognosis (p = 0.02). A direct association of CD47 expression by cancer cells and the % FOXP3+ TILs (p = 0.01, r = 0.25) was also noted.
Conclusions:
TAMs play an important role in the prognosis of operable NSCLC. As SIRPα+ macrophages adversely affect prognosis, it is suggested that the CD47/SIRPα axis is a sound target for adjuvant immunotherapy policies, aiming to improve the cure rates in operable NSCLC.
Insights
Cancer cells use CD47 to evade immune cells. Targeting the CD47/SIRPα pathway in non-small cell lung cancer (NSCLC) may improve immunotherapy outcomes by modulating tumor-associated macrophages (TAMs).
Area of Science:
- Immunology and Oncology
- Tumor Microenvironment
- Cancer Immunotherapy
Background:
- Cancer cells evade macrophage phagocytosis via CD47 expression, which binds to SIRPα on macrophages.
- The CD47/SIRPα pathway is a target for cancer immunotherapy currently under clinical investigation.
Purpose of the Study:
- To investigate the expression of CD47 and SIRPα in non-small cell lung cancer (NSCLC).
- To correlate CD47/SIRPα expression with tumor-infiltrating immune cells and patient prognosis.
Main Methods:
- Analysis of CD47/SIRPα expression in 98 NSCLC samples.
- Assessment of tumor stroma infiltration by CD68+ macrophages, TILs, and PD-L1/PD-1.
- Correlation of molecular markers with overall survival and clinicopathological features.
Main Results:
- CD47 was highly expressed on cancer cells in 29% of cases.
- High CD68 macrophage score correlated with improved overall survival, independent of stage.
- High SIRPα expression on macrophages was linked to CD47 expression, low TILs, and poor prognosis.
Conclusions:
- Tumor-associated macrophages (TAMs) significantly impact NSCLC prognosis.
- SIRPα-expressing macrophages are associated with adverse outcomes, highlighting the CD47/SIRPα axis as a therapeutic target.
- Targeting the CD47/SIRPα pathway could enhance adjuvant immunotherapy for operable NSCLC and improve cure rates.
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