Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer

Abstract

The aim of the present study was to investigate the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs), CD8+ CTLs and Tregs/CD8+ ratios in gastric cancer patients after R0 resection. From 133 patients, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. The prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff, while the effects of Foxp3+/CD8+ ratios were evaluated using the value determined by ROC cure analysis as cutoff. It was found that CD4+ and CD8+ TILs were not associated with overall survival (OS). In the tumor sites, higher Foxp3+ Tregs/CD8+ ratio was an independent factor for worse OS (multivariate analysis HR = 2.827, P = 0.037). The 1-year, 2-year and 3-year OS rates were 90, 77.5 and 70% for the group with intratumoral high Tregs/CD8+ ratio, compared with 100, 94.3 and 90.5% for the group with intratumoral low ratio. At the same time, the presence of intratumoral high Foxp3+ Tregs was also associated with worse OS (log rank test, P = 0.025); however, it was not an independent predictor and correlated with intratumoral Foxp3+ Tregs/CD8+ ratio (chi(2) test, P < 0.001). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph node metastasis (P = 0.028), it was not associated with prognosis (P = 0.458). Intratumoral high Foxp3+ Tregs/CD8+ ratio was an independent predictor for the prognosis of gastric cancer. It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.