The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients.

Han Sol Choi,Jae Moon Bae,Soo Min Ahn,Kyoung-Mee Kim,Tae Sung Sohn,Min Gew Choi,Hye-Mi Kim,Sung Kim,Eun-Suk Kang,Myung-Soo Kang,Joon Ho Lee,Sang Yun Ha

doi:10.18632/oncotarget.6958

Abstract

The prognostic effects of tumor infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs) and myeloid derived suppressing cells (MDSCs) are inconclusive in gastric cancers. We investigated the frequencies of TILs including CD8+ T cells, CD45+CD4+CD25± FOXP3+ Tregs, CD45+CD11b+ CD14+ HLA−DR− MDSCs in 28 gastric cancer tissues by using multicolor flow cytometry. In gastric cancer tissue, the percentage of Tregs among the CD4+ T cell subset was substantially increased compared to that of Tregs among peripheral blood CD4+ T cells from the controls. High frequency of CD8+ T cells among CD3+ T cells correlated with increased overall survival (OS) (p = 0.005). High frequency of Tregs among CD4+ T cells correlated with increased OS (p < 0.001), and disease-free survival (DFS) (p = 0.039) and was an independent prognostic factor in OS (Hazard ratio: 0.047; 95% confidence interval, 0.006-0.372; p = 0.004). High frequency of MDSCs among total examined cells correlated with decreased OS (p = 0.027) and was an independent prognostic factor in OS (Hazard ratio 8.601; 95% confidence interval, 1.240-59.678; p = 0.029). We have demonstrated that high levels of Tregs among tumor-infiltrating CD4+ T cells were favorable, but an increased proportion of MDSCs was an adverse independent prognostic factor in gastric cancer. Our results may provide important insights for future immunotherapy in gastric cancer.

Highlights

Gastric cancer (GC) is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related deaths worldwide [1, 2]
Many studies have shown that a high density of Tregs, which usually evaluated by quantification of Forkhead box protein P3 (FOXP3)+ T cells by using immunohistochemistry (IHC), was associated with a poor outcome, and these results were explained on the basis of the suppressive effects of Tregs on antitumor cytotoxic T cells [24,25,26]
We examined the frequencies of tumor infiltrating immune cell subsets by multi-color flow cytometry, which enabled us to define more specific roles of immune cells as well as more objective quantification in GC, and investigated the clinical significance of immune cells, especially Treg and myeloid derived suppressing cells (MDSCs)

Summary

Introduction

Gastric cancer (GC) is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related deaths worldwide [1, 2]. Infiltration of CD8+ cytotoxic T cells into tumors has been reported as a favorable prognostic factor in many cancers including GCs [9,10,11,12,13,14,15,16,17]. Many studies have shown that a high density of Tregs, which usually evaluated by quantification of FOXP3+ T cells by using immunohistochemistry (IHC), was associated with a poor outcome, and these results were explained on the basis of the suppressive effects of Tregs on antitumor cytotoxic T cells [24,25,26]. The controversial prognostic significance of Tregs may differ depending on the specific tumor types. Many studies reported Tregs as adverse prognostic factor in GC [25, 27,28,29], while several opposite results suggesting Tregs as a favorable prognostic factor have been reported so far [18, 30, 31]

Methods

Results

Conclusion