Elsevier

European Journal of Cancer

Volume 44, Issue 13, September 2008, Pages 1875-1882
European Journal of Cancer

Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer

https://doi.org/10.1016/j.ejca.2008.05.017Get rights and content

Abstract

We investigated the clinical significance of tumour-infiltrating FOXP3-positive regulatory T cells (Tregs) in radically resected (R0) gastric cancer. From a single-institution database, tumors of 110 patients who underwent R0 resection for stage II–III disease were studied for FOXP3-positive Tregs by immunohistochemistry. The observed median number of FOXP3-positive Tregs was used as the cut-point in analyses (<6 versus ⩾6 count). Tregs were significantly higher in gastric carcinomas than in normal tissue (P = 0.0001). Tregs count ⩾6 was significantly associated with vascular/lymphatic/perineural invasion (VELIPI) in the tumour (P = 0.03). Multivariate analysis showed association between adverse relapse-free survival and grading 3, stage III, VELIPI and Tregs count ⩾6 (P = 0.02). Adverse overall survival was associated with grading 3, stage III, VELIPI and Tregs count ⩾6 (P = 0.006). FOXP3-positive Tregs may be a novel marker for identifying high-risk gastric cancer patients. Present findings deserve additional investigation as Tregs may also represent an innovative therapeutic target.

Introduction

Tumours often contain infiltrates of immune cells. These infiltrates represent the result of an interplay between the host immune system and tumours during their development and growth.1 Intratumoural T cells with an effector (memory) phenotype showed favourable influence on the prognosis of patients with colorectal2, 3 and epithelial ovarian cancer.4 On the other hand, tumours have elaborated methods to circumvent such a response. T regulatory (Treg) cells are functionally defined as T cells that inhibit an immune response by influencing the activity of another cell type.5 Treg cells fall into two main categories. One is naturally occurring thymus-derived CD4+ T cells; the other is peripherally antigen-induced CD4+ T cells deriving from CD4+CD25- non-Treg T cells. Treg cells, which were originally defined by CD4 and CD25hi positivity, have been identified in peripheral blood, primary tumours and draining lymph nodes of cancer patients.5 The body of evidence suggests that Treg cells within the tumour microenvironment might play a significant role in the suppression of local antitumour immune responses.5 This may also explain why the presence of high numbers of intratumoural FOXP3-positive T cells has been associated with a higher risk of recurrence and poor overall survival of patients with some solid neoplasms.6, 7, 8, 9, 10, 11, 12 Thus, Tregs are under investigation as a potential prognostic factor and they may also represent a novel therapeutic target in several cancers. In this perspective, a major issue concerns their precise identification and the possibility of selectively targeting these cells for therapeutic purposes. In fact, CD25 is expressed by all activated effector T cells. Other markers (e.g. CTLA-4, GITR, FOXP3) have been proposed to identify Tregs, but their expression is not exclusively restricted to Tregs. Nonetheless, FOXP3 has been widely accepted as the best marker for Treg identification in humans thus far.13, 14

CD4+ CD25+ and/or FOXP3+ Treg cell have been identified in the peripheral blood,15, 16, 17 ascitic fluid,15 primary tumours and draining lymph nodes16, 18, 19 of gastric cancer patients. A higher percentage of Treg cells have been found in the peripheral blood of gastric cancer patients than healthy controls.15, 16, 17 The presence of these cells may thus represent an unfavourable feature. Despite radical surgery, a significant proportion of patients with locally advanced gastric cancer relapse and die. Also, the role of adjuvant chemotherapy for these patients is controversial.20 The principal aim of this study was to establish whether intratumoural FOXP3-positive T cell count adds prognostic information after considering traditional clinico-pathologic features of patients with radically resected, stage II–III gastric cancer.

Section snippets

Patients

Tissues from gastric adenocarcinomas used in this retrospective study represent a consecutive series of patients from the referral population of a regionally-based cancer service and they were collected from patients undergoing surgery at the Azienda Ospedale San Salvatore (Pesaro, Italy). From 1997 to 2006, 307 patients underwent radical surgery (R0) for gastric adenocarcinoma. This study targeted a high-risk population of stage II–III patients. In planning the study we incorporated the

Results

The characteristics of the 110 studied patients are shown in Table 1. In this study, 48 patients (44%) died with positive cytological or histological confirmation of recurrent disease. All 48 relapsed patients underwent 5-fluorouracil/cisplatin-based palliative chemotherapy.

In the 110 cases, the median for the FOXP3-positive lymphocyte count was 6; (minimum–maximum, 0–49.5). The number of cases with median FOXP3-positive cells <6 and ⩾6 was 52 (47%) and 58 (53%), respectively. In 64 cases (58%)

Discussion

Our study shows a significant increase in the FOXP3-positive T cell number in gastric adenocarcinomas as compared with surrounding normal tissue. This difference has also been observed in other solid tumours, e.g. hepatocellular carcinoma, colorectal, breast, pancreatic, non-small cell lung cancer6, 7, 8, 9, 10, 11, 12, 23, 24, 25 and likely reflects immunological tumour–host interactions at the tumour site. Studies in prostate,26 ovarian8 and gastric27 carcinomas showed Tregs recruitment into

Conflict of interest statement

None declared.

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