CD47 overexpression is associated with decreased neutrophil apoptosis/phagocytosis and poor prognosis in non-small-cell lung cancer patients

Abstract

Background:Non-small-cell lung cancer (NSCLC) patients often exhibit neutrophilia, which has been associated with poor clinical outcomes. However, the mechanisms that lead to neutrophilia have not been fully established. CD47 is an antiphagocytic molecule that promotes neutrophil recruitment.Methods:Blood was collected from 50 treatment-naive patients with advanced NSCLC and from 25 healthy subjects. The frequency of CD66b+ cells and the expression of CD47 were determined by flow cytometry. Neutrophil apoptosis was determined by 7-amino-actinomycin D/Annexin V-APC staining. Phagocytosis was assessed by flow cytometry. Reactive oxygen species production after phorbol 12-myristate 13-acetate treatment was quantified by 2′,7′-dichlorofluorescein fluorescence. Pro-inflammatory plasma cytokines were quantified using a cytometric bead array assay.Results:The percentage of circulating neutrophils was significantly higher in patients than in controls (P<0.001). Patient-derived neutrophils had a higher oxidative potential than those of controls (P=0.0286). The number of neutrophils in late apoptosis/necrosis was lower in patients than in controls (P=0.0317). Caspase 3/7 activation was also lower in patients than in controls (P=0.0079). CD47 expression in whole-blood samples and in the neutrophil fraction was higher in NSCLC patients than in controls (P=0.0408 and P<0.001). Patient-derived neutrophils were phagocytosed at a lower rate than those of controls (P=0.0445). CD47 expression in neutrophils negatively correlated with their ingestion by macrophages (P=0.0039). High CD47 expression was associated with a lower overall survival.Conclusions:Increased CD47 expression on the surface of neutrophils was associated with a delay in neutrophil apoptosis and with an impairment in their phagocytic clearance by macrophages, suggesting that CD47 overexpression may be one of the underlying mechanisms leading to neutrophilia in NSCLC patients.

Association between CD47 expression, clinical characteristics and prognosis in patients with advanced non‐small cell lung cancer

“…Inhibition of phagocytosis occurs when CD47 binds to signal regulatory protein alpha (SIRPα) expressed on the macrophage surface . CD47 overexpression is associated with growth and progression in various cancer types such as non‐Hodgkin's lymphoma, gastric, colorectal, bladder, breast cancer and NSCLC . We have previously reported that CD47 overexpression in whole‐blood samples from NSCLC patients is associated with poor OS, and its expression on neutrophil surface prevents apoptosis and phagocytic clearance of these cells .…”

“…12,13 CD47 overexpression is associated with growth and progression in various cancer types such as non-Hodgkin's lymphoma, gastric, colorectal, bladder, breast cancer and NSCLC. [14][15][16] We have previously reported that CD47 overexpression in whole-blood samples from NSCLC patients is associated with poor OS, and its expression on neutrophil surface prevents apoptosis and phagocytic clearance of these cells. 14 Use of anti-CD47 antibodies for treatment of non-Hodgkin lymphoma, breast, bladder, and ovarian carcinomas has shown promising results.…”

“…[14][15][16] We have previously reported that CD47 overexpression in whole-blood samples from NSCLC patients is associated with poor OS, and its expression on neutrophil surface prevents apoptosis and phagocytic clearance of these cells. 14 Use of anti-CD47 antibodies for treatment of non-Hodgkin lymphoma, breast, bladder, and ovarian carcinomas has shown promising results. 12,[17][18][19][20] However, data regarding CD47 expression and its potential relation with clinical outcomes in lung cancer patients remain limited.…”

Targeting CD47 in Sézary syndrome with SIRPαFc

“…8,35,36 Additionally, several studies have shown that high CD47 expression in tumors correlates with poor prognosis. 37 However, little is known about the role of CD47 in SS. Using TCR Vb staining to identify the dominant clone, we demonstrate that malignant lymphocytes (clonal Vb 1 CD4 1 ) express high levels of CD47 compared with nonmalignant lymphocytes in the same patient with SS.…”

Role of negative regulation of immune signaling pathways in neutrophil function

“…In particular binding of CD47 to SIRPα induces ITIM phosphorylation and recruitment of SHP-1 and SHP-2 ultimately resulting in the inhibition of PMN apoptosis [77]. As such, increased PMN surface expression of CD47 is associated with a delay in apoptosis and poor prognosis in non-small cell lung cancer patients [78]. Finally, recent studies have demonstrated that sialylated erythrocyte surface glycans engage the inhibitory immunoreceptor Siglec 9 on circulating PMN to suppress activation and apoptosis [65].…”