Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype
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 I...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000339.full |
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| author | Jun Wang Hongliang Dong Yueyao Yang Chenhui Gao Hehe Sun Hongmin Wang Chao Hong Fangyuan Gong Xiaoming Gao |
| author_facet | Jun Wang Hongliang Dong Yueyao Yang Chenhui Gao Hehe Sun Hongmin Wang Chao Hong Fangyuan Gong Xiaoming Gao |
| author_sort | Jun Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a484333bb3044dc4b63e641e296f0dc0 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a484333bb3044dc4b63e641e296f0dc02025-08-20T02:49:52ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000339Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotypeJun Wang0Hongliang Dong1Yueyao Yang2Chenhui Gao3Hehe Sun4Hongmin Wang5Chao Hong6Fangyuan Gong7Xiaoming Gao8Jin-feng Laboratory, Chongqing, Chongqing, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaInstitute of Biology and Medical Sciences, School of Biology and Basic Medical Science, Soochow University, Suzhou, ChinaGlobal Health and Population Research, FHI 360, Durham, North Carolina, USABackground 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.https://jitc.bmj.com/content/8/1/e000339.full |
| spellingShingle | Jun Wang Hongliang Dong Yueyao Yang Chenhui Gao Hehe Sun Hongmin Wang Chao Hong Fangyuan Gong Xiaoming Gao Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype Journal for ImmunoTherapy of Cancer |
| title | Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype |
| title_full | Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype |
| title_fullStr | Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype |
| title_full_unstemmed | Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype |
| title_short | Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype |
| title_sort | lactoferrin containing immunocomplex mediates antitumor effects by resetting tumor associated macrophages to m1 phenotype |
| url | https://jitc.bmj.com/content/8/1/e000339.full |
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