title: ICOS+Foxp3+TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori.
abstract: Regulatory T cells (Tregs) have an immunosuppressive role in the tumor microenvironment. Since effector Tregs (eTregs), which have highly suppressive functions, are located in a subpopulation of Foxp3+CD4+Tregs, the TCR-inducible costimulatory receptor (ICOS) was applied as a marker of eTregs that infiltrated gastric cancer tissue and the induction pathway of ICOS+Foxp3+cells was analyzed by flow cytometry and immunohistochemistry. In tumor-infiltrating lymphocytes (TILs), ICOS+Foxp3+CD4+T cells were abundantly observed in the late stages of gastric cancer. ICOS+CD4+TILs exhibited the ability to produce IL-10, but not IFN-γ, TNF, or IL-17 and also to suppress the proliferation of CFSE-labeled responder CD8+T cells. With the agonistic ICOS-L protein (rICOS-L Ig), ICOS+Foxp3+cells were efficiently induced from naive CD4+T cells under a stimulation with TGF-β and CD3/CD28 mAbs. Furthermore, when A*0201 PBMCs were cultured with the CMV or Melan-A antigenic peptide and rICOS-L Ig, the induction of CMV or Melan-A tetramer-binding CD8+T cells, respectively, was inhibited. The expression of ICOS in Foxp3+cells was closely related to plasmacytoid dendritic cells (pDCs) and their expression of ICOS-L and TLR9 as well as Helicobacter pylori infection. Collectively, our results demonstrate the potential of ICOS as a promising target for direct Treg-targeting therapeutic agents for gastric cancer, and that of eradicating therapy for H. pylori as an indirect immune therapy for gastric cancer.
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Tomohira
authors.initials: T
authors.lastname: Takeoka
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Urakawa
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Morimoto-Okazawa
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Atsunari
authors.initials: A
authors.lastname: Kawashima
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Iwahori
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takiguchi
authors.affiliation: Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.affiliation: Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wada
mesh_terms: D014408:Biomarkers, Tumor / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016481:Helicobacter Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018106:CD28 Antigens; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: Foxp3; ICOS ligand; TIL; TLR9; pDC