Expression of CD47 and SIRPα Macrophage Immune-Checkpoint Pathway in Non-Small-Cell Lung Cancer

Background: Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRP alpha ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development. Methods: We investigated the expression of CD47/SIRP alpha 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. SIRP alpha and CD68 were expressed, to a varying extent, by tumor-associated macrophages (M phi, TAMs). A high CD68M phi-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 SIRP alpha expression by CD68+ TAMs (SIRP alpha/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 SIRP alpha+ macrophages adversely affect prognosis, it is suggested that the CD47/SIRP alpha+ axis is a sound target for adjuvant immunotherapy policies, aiming to improve the cure rates in operable NSCLC.

Automated summary

The study showed that high CD47 expression by cancer cells, along with high SIRPα expression by CD68+ TAMs, low TIL-score, and poor prognosis are correlated in NSCLC. CD68+ TAMs play an important role in the prognosis of operable NSCLC. Targeting the CD47/SIRPα axis may improve adjuvant immunotherapy strategies in NSCLC.