Abstract 1519: The impact of ICOS+ Tregs on prognosis of gastric cancer patients

Abstract

Abstract Background and Aim: Foxp3+ CD4+ regulatory T cells (Tregs) have a suppressive role in antitumor immunity. Among Foxp3+ CD4+ population, effector Tregs (eTregs) with highly suppressive functions are located in a subpopulation of Tregs. We have reported that ICOS has the potential as a novel marker for eTregs in gastric cancer (GC) and ICOS+ Tregs were abundant in H. pylori (HP) Ab-positive GC patients. In the present study, we investigate whether HP induce ICOS+ Tregs in GC. Materials and Methods: Tumor-infiltrating lymphocytes (TILs), normal mucosa-infiltrating lymphocytes (NILs) and peripheral blood mononuclear cells (PBMCs) were obtained from 117 gastric cancer patients. Tregs, ICOS+ Tregs, linage- CD11c- CD123+ HLA-DR+ plasmacytoid dendritic cells (pDCs), TLR9+pDCs, ICOS-L+ pDCs were analyzed by flow cytometry and multicolor immunohistochemistry. HP Ab was analyzed by ELISA. For induction assay of ICOS+ Tregs, naïve CD4 T cells were cultured with pDCs under stimulation with TGF-β, CD3/CD28 mAbs and frozen-and-thawed HP (NCTC11637). Results: In GC tissues, %ICOS-L in pDCs was positively correlated with %ICOS in Tregs (r2=0.52, p<0.001). %TLR9 in pDCs and %ICOS-L in pDCs were significantly higher in HP Ab-positive patients than others (p=0.001 and p=0.042, respectively). %ICOS+ in Tregs was significantly higher in HP-Ab positive patients than others (p=0.020). By multicolor immunohistochemistry, a large number of ICOS/Foxp3 double positive cells were observed. In induction assay, addition of HP (NCTC11637) increased the expression of ICOS-L in pDC and induction of ICOS+ Tregs, which were suppressed by TLR9 antagonist. %ICOS+ in Tregs were significantly lower in HP-eradicated patients than others (p<0.001). Interestingly, %ICOS+ in Tregs were also significantly lower in patients eradicated within four weeks before their surgical treatments (p<0.001). Conclusion: Our results indicate the induction pathway from HP to ICOS+ Tregs mediated by TLR9 and ICOS-L in pDCs. Preoperative eradication for HP may have a potential as an indirect immune therapy for gastric cancer patients. Citation Format: Shinya Urakawa, Hisashi Wada, Masaki Mori, Yuichiro Doki. The impact of ICOS+ Tregs on prognosis of gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1519.