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

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-, 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- 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. What's new? Immune tolerance within the tumor microenvironment is mediated in part by regulatory T-cells (Tregs), a key transcription factor for which is Foxp3. The immunosuppressive activity of Tregs is further bolstered by expression of inducible costimulatory receptor (ICOS). Here, ICOS+ Foxp3(+) CD4(+) tumor-infiltrating lymphocytes (TILs) exhibited greater levels of immunosuppressive activity compared with ICOS-TILs in cells isolated from patients with gastric cancer. Both ICOS expression and increased %ICOS+ TILs were closely related to disease progression and prognosis. Moreover, in plasmacytoid dendritic cells, ICOS ligand and toll-like receptor 9 expression were associated with Helicobacter pylori infection and %ICOS+ TILs.