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 language | English |
|---|---|
| Pages (from-to) | 686-695 |
| Number of pages | 10 |
| Journal | International Journal of Cancer |
| Volume | 140 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 1 2017 |
| Externally published | Yes |
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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 journal › Article
}
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.
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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 -