title: The key role of IL-6-arginase cascade for inducing dendritic cell-dependent CD4(+) T cell dysfunction in tumor-bearing mice.
abstract: Evaluation of immune dysfunction during the tumor-bearing state is a critical issue in combating cancer. In this study, we initially found that IL-6, one of the cachectic factors, suppressed CD4(+) T cell-mediated immunity through downregulation of MHC class II by enhanced arginase activity of dendritic cells (DC) in tumor-bearing mice. We demonstrated that administration of Ab against IL-6R (anti-IL-6R mAb) greatly enhanced T cell responses and inhibited the growth of tumor in vivo. We also found that IL-6 upregulated the expression of arginase-1 and arginase activity of DC in vitro. Tumor-infiltrating CD11c(+) DC exhibited upregulated mRNA expression of arginase-1 but reduced expression of MHC class II in parallel with the increase in serum IL-6 levels at the late stage in tumor-bearing hosts. However, the administration of anti-IL-6R mAb into tumor-bearing mice inhibited both the downmodulation of MHC class II and the upregulation of arginase-1 mRNA levels in DC. Furthermore, we noted that N(ω)-hydroxy-L-arginine or L-arginine, an arginase-1 inhibitor, blocked the reduction in MHC class II levels on CD11c(+) DC during the tumor-bearing state. Finally, we demonstrated that the administration of N(ω)-hydroxy-L-arginine at the peritumor site significantly enhanced CD4(+) T cell responses and inhibited tumor growth. Thus, IL-6-mediated arginase activation and the subsequent reduction in MHC class II expression on DC appeared to be critical mechanisms for inducing dysfunction of the immune system in the tumor-bearing state. Blockade of the IL-6-arginase cascade is a promising tool to overcome the dysfunction of antitumor immunity in tumor-bearing hosts.
authors.affiliation: Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Narita
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Kitamura
authors.forename: Daiko
authors.initials: D
authors.lastname: Wakita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sumida
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Masuko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Terada
authors.forename: Kiichiroh
authors.initials: K
authors.lastname: Nakano
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D001120:Arginine; D001119:Arginase