title: M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells.
abstract: Monocytes attracted by tumor-induced chronic inflammation differentiate to APCs, the type of which depends on cues in the local tumor milieu. In this work, we studied the influence of human cervical cancer cells on monocyte differentiation and showed that the majority of cancer cells either hampered monocyte to dendritic cell differentiation or skewed their differentiation toward M2-like macrophages. Blocking studies revealed that M2 differentiation was caused by tumor-produced PGE(2) and IL-6. TGF-β, IL-10, VEGF, and macrophage colony-stimulating factor did not play a role. Notably, these CD14(+)CD163(+) M2 macrophages were also detected in situ. Activation of cancer cell-induced M2-like macrophages by several TLR-agonists revealed that compared with dendritic cells, these M2 macrophages displayed a tolerogenic phenotype reflected by a lower expression of costimulatory molecules, an altered balance in IL-12p70 and IL-10 production, and a poor capacity to stimulate T cell proliferation and IFN-γ production. Notably, upon cognate interaction with Th1 cells, these tumor-induced M2 macrophages could be switched to activated M1-like macrophages that expressed high levels of costimulatory molecules, produced high amounts of IL-12 and low amounts of IL-10, and acquired the lymphoid homing marker CCR7. The effects of the interaction between M2 macrophages and Th1 cells could partially be mimicked by activation of these APCs via CD40 in the presence of IFN-γ. Our data on the presence, induction, and plasticity of tumor-induced tolerogenic APCs in cervical cancer suggest that tumor-infiltrated Th1 cells can stimulate a tumor-rejecting environment by switching M2 macrophages to classical proinflammatory M1 macrophages.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Moniek
authors.initials: M
authors.lastname: Heusinkveld
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: de Vos van Steenwijk
authors.forename: Renske
authors.initials: R
authors.lastname: Goedemans
authors.forename: Tamara H
authors.initials: TH
authors.lastname: Ramwadhdoebe
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000502:physiology*; D005260:Female; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000276:immunology; D052161:Human papillomavirus 18 / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000145:classification / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D030361:Papillomavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000093242:Interleukin-6 Inhibitors
chemical_list: D019138:Antibodies, Blocking; D015232:Dinoprostone; D018836:Inflammation Mediators; D018664:Interleukin-12; D015850:Interleukin-6; D009363:Neoplasm Proteins; D000093242:Interleukin-6 Inhibitors