title: Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression.
abstract: IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4+T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b+cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8+T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4+T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy.Cancer Res; 77(9); 2279-91. ©2017 AACR.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan. htsukamo@kumamoto-u.ac.jp mxnishim@gpo.kumamoto-u.ac.jp.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.|Department of Orthopaedic Surgery, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujieda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Department of Clinical Research Center, Faculty of Life Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Tokunori
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yuno
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Fukuma
authors.affiliation: Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Orthopaedic Surgery, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuta
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan. htsukamo@kumamoto-u.ac.jp mxnishim@gpo.kumamoto-u.ac.jp.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D051379:Mice; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics*; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018417:Th1 Cells
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D019947:Receptors, Interleukin-6