title: Lewis Lung Cancer Cells Promote SIGNR1(CD209b)-Mediated Macrophages Polarization Induced by IL-4 to Facilitate Immune Evasion.
abstract: Tumor-associated macrophages are a prominent component of lung cancer and contribute to tumor progression by facilitating the immune evasion of cancer cells. DC-SIGN (CD209) assists in the immune evasion of a broad spectrum of pathogens and neoplasms by inhibiting the maturation of DCs and subsequent cytokines production. However, the expression of DC-SIGN in macrophages and its role in mediating immune evasion in lung cancer and the underlying mechanism remain unclear. Our study aimed to identify the immunosuppressive role of SIGNR1 in murine macrophage differentiation and lung cancer progression. We found that SIGNR1-positive RAW264.7 macrophages were enriched in mixed cultures with Lewis lung cancer cells (LLC) (ratio of RAW 264.7 to LLC being 1:1) after stimulation with IL-4. Moreover, LLC-educated macrophages exhibited significantly higher levels of IL-10 but lower IL-12 in response to IL-4 treatment as determined by RT-PCR and ELISA. However, inhibition of SIGNR1 markedly hampered the production of IL-10, indicating that SIGNR1 was indispensable for IL-4+LLC induced macrophage polarization towards the M2 subtype. Furthermore, polarized M2 cells immersed in a tumor microenvironment promoted the migration of LLCs, as measured by transwell assays, but migration was suppressed after blockade of SIGNR1 using CD209b antibody. In addition, IL-4+LLC-educated macrophages reduced the proliferation of the activated T cells and reduced IFN-γ-mediated Th1 response in T cells, while SIGNR1 inhibition rescued Th1 cell functions. In conclusion, murine SIGNR1 expressed in LLC-educated macrophages appears to mediate IL-4-induced RAW264.7 macrophage polarization and thus facilitate lung cancer evasion.
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Wenhai
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Respiration Medicine, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Respiration Medicine, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Enqing
authors.initials: E
authors.lastname: Fu
authors.affiliation: Department of Respiration Medicine, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Respiration Medicine, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Respiration Medicine, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, Shaanxi Province, China.
authors.forename: Deguang
authors.initials: D
authors.lastname: Mu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D019138:Antibodies, Blocking; D015815:Cell Adhesion Molecules; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
keywords: IL-4; IMMUNE EVASION; LUNG CANCER; MURINE MACROPHAGE POLARIZATION; SIGNR1