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 journalArticlepeer-review

94 Citations (Scopus)


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
Issue number3
Publication statusPublished - Feb 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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