Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype.

Abstract

BACKGROUND:

Tumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy.

METHODS:

A mouse IgG1 (kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+ monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models.

RESULTS:

Through coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues.

CONCLUSIONS:

LTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.

• Authors: Hongliang Dong, Yueyao Yang, Chenhui Gao, Hehe Sun, Hongmin Wang, Chao Hong, Jun Wang, Fangyuan Gong, Xiaoming Gao
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 1 (03 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32217759 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Monoclonal
• Antigen-Antibody Complex
• Culture Media, Conditioned
• Cytokines
• LTF protein, human
• Lactoferrin

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antigen-Antibody Complex (immunology)
• Cell Line, Tumor
• Coculture Techniques
• Culture Media, Conditioned
• Cytokines (immunology)
• Disease Models, Animal
• Humans
• Lactoferrin (immunology)
• Macrophages (drug effects, immunology, metabolism)
• Melanoma, Experimental (drug therapy, immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Phenotype
• T-Lymphocytes, Regulatory (immunology)