Abstract
Lactoferrin (LF) is a soluble glycoprotein of the transferring family found in most biological fluids, functioning as a major first line defense molecule against infection in mammals. It also shows certain anti-tumor activity, but its clinical application in tumor therapy is limited because high dosage is required. In this study, we demonstrate that M860, a monoclonal antibody against human LF (hLF), could significantly increase the anti-tumor potential of low dosage hLF by forming LF-containing immune complex (IC). Human monocytes primed with LF-IC, but not hLF or M860 alone, or control ICs, showed strong tumoricidal activity on leukemia cell lines Jurkat and Raji through induction of secreted Granzyme B (GzB). LF-IC is able to colligate membrane-bound CD14 (a TLR4 co-receptor) and FcγRIIa (a low affinity activating Fcγ receptor) on the surface of human monocytes, thereby triggering the Syk-PI3K-AKT-mTOR pathway leading to GzB production. Our work identifies a novel pathway for LF-mediated tumoricidal activity and may extend the clinical application of LF in tumor therapy.
Highlights
Lactoferrin (LF), an 80-kDa glycoprotein with iron-binding ability, was discovered in mammary secretions and in the second granules of neutrophils, and could be extracellularly released under conditions of stress or inflammation [1]
Based upon our previous findings that LF-immune complex (IC) induces a large amount of TNF-α production by human monocytes via co-ligation of CD14/TLR4 and FcγRIIa (CD32a) [19], we hypothesized that
Concentration of Granzyme B (GzB) in the supernatant of LF-IC primed monocyte cultures was unaffected by the presence of these tumor cells (Figure 3F)
Summary
Lactoferrin (LF), an 80-kDa glycoprotein with iron-binding ability, was discovered in mammary secretions and in the second granules of neutrophils, and could be extracellularly released under conditions of stress or inflammation [1]. It functions as a major defense molecule against infections, and exhibits certain anti-tumor potential both in vitro and in vivo [2,3]. LF is widely used for various clinical conditions It is utilized for treating stomach and intestinal ulcers [11,12]. Clinical application of LF in tumor therapy is limited because of fast clearance of LF in vivo and high dosage requirement for effective therapy [16,17]
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