ICOS + Foxp3 + TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori

Hirotsugu Nagase, Tomohira Takeoka, Shinya Urakawa, Akiko Morimoto-Okazawa, Atsunari Kawashima, Kota Iwahori, Shuji Takiguchi, Hiroyoshi Nishikawa, Eiichi Sato, Shimon Sakaguchi, Masaki Mori, Yuichiro Doki, Hisashi Wada

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)686-695
Number of pages10
JournalInternational Journal of Cancer
Volume140
Issue number3
DOIs
Publication statusPublished - Feb 1 2017
Externally publishedYes

Fingerprint

Tumor-Infiltrating Lymphocytes
Regulatory T-Lymphocytes
Helicobacter pylori
Stomach Neoplasms
MART-1 Antigen
T-Lymphocytes
CD4 Antigens
Toll-Like Receptor 9
Tumor Microenvironment
Interleukin-17
Helicobacter Infections
Immunosuppressive Agents
Interleukin-10
Dendritic Cells
Flow Cytometry
Therapeutics
Immunohistochemistry
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

ICOS + Foxp3 + TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori . / Nagase, Hirotsugu; Takeoka, Tomohira; Urakawa, Shinya; Morimoto-Okazawa, Akiko; Kawashima, Atsunari; Iwahori, Kota; Takiguchi, Shuji; Nishikawa, Hiroyoshi; Sato, Eiichi; Sakaguchi, Shimon; Mori, Masaki; Doki, Yuichiro; Wada, Hisashi.

In: International Journal of Cancer, Vol. 140, No. 3, 01.02.2017, p. 686-695.

Research output: Contribution to journalArticle

Nagase, H, Takeoka, T, Urakawa, S, Morimoto-Okazawa, A, Kawashima, A, Iwahori, K, Takiguchi, S, Nishikawa, H, Sato, E, Sakaguchi, S, Mori, M, Doki, Y & Wada, H 2017, ' ICOS + Foxp3 + TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori ', International Journal of Cancer, vol. 140, no. 3, pp. 686-695. https://doi.org/10.1002/ijc.30475
Nagase, Hirotsugu ; Takeoka, Tomohira ; Urakawa, Shinya ; Morimoto-Okazawa, Akiko ; Kawashima, Atsunari ; Iwahori, Kota ; Takiguchi, Shuji ; Nishikawa, Hiroyoshi ; Sato, Eiichi ; Sakaguchi, Shimon ; Mori, Masaki ; Doki, Yuichiro ; Wada, Hisashi. / ICOS + Foxp3 + TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori In: International Journal of Cancer. 2017 ; Vol. 140, No. 3. pp. 686-695.
@article{da5a1235cf004ea497bf2c7939702123,
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.",
author = "Hirotsugu Nagase and Tomohira Takeoka and Shinya Urakawa and Akiko Morimoto-Okazawa and Atsunari Kawashima and Kota Iwahori and Shuji Takiguchi and Hiroyoshi Nishikawa and Eiichi Sato and Shimon Sakaguchi and Masaki Mori and Yuichiro Doki and Hisashi Wada",
year = "2017",
month = "2",
day = "1",
doi = "10.1002/ijc.30475",
language = "English",
volume = "140",
pages = "686--695",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - ICOS + Foxp3 + TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori

AU - Nagase, Hirotsugu

AU - Takeoka, Tomohira

AU - Urakawa, Shinya

AU - Morimoto-Okazawa, Akiko

AU - Kawashima, Atsunari

AU - Iwahori, Kota

AU - Takiguchi, Shuji

AU - Nishikawa, Hiroyoshi

AU - Sato, Eiichi

AU - Sakaguchi, Shimon

AU - Mori, Masaki

AU - Doki, Yuichiro

AU - Wada, Hisashi

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84997831652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84997831652&partnerID=8YFLogxK

U2 - 10.1002/ijc.30475

DO - 10.1002/ijc.30475

M3 - Article

VL - 140

SP - 686

EP - 695

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 3

ER -