It has been reported that an increased population of regulatory T cells (Tregs) is one of the reasons for impaired anti-tumor immunity. Recently, Foxp3 has been reported as a reliable marker of Tregs. The authors investigated the frequency of Foxp3 1 Tregs within CD4 1 cells in TILs, regional lymph nodes and PBLs of gastric cancer patients (n 5 45). Furthermore, to elucidate the mechanisms behind Treg accumulation within tumors, they evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3 1 Tregs in gastric cancer. CD4 1 CD25 1 Foxp3 1 Tregs as a percentage of CD4 1 cells were counted by flow cytometry and evaluated by immunohistochemistry. Moreover, an in vitro migration assay using Tregs derived from gastric cancers was performed in the presence of CCL17 or CCL22. As a result, the frequency of Foxp3 1 Tregs in TILs was significantly higher than that in normal gastric mucosa (12.4% 6 7.5% vs. 4.1% 6 5.3%, p < 0.01). Importantly, the increase in Tregs in TILs occurred to the same extent in early and advanced disease. Furthermore, the frequency of CCL17 1 or CCL22 1 cells among CD14 1 cells within tumors was significantly higher than that of normal gastric mucosa, and there was a significant correlation between the frequency of CCL17 1 or CCL22 1 cells and Foxp3 1 Tregs in TILs. In addition, the in vitro migration assay indicated that Tregs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3 1 Tregs, with such an observation occurring in early gastric cancer. ' 2008 Wiley-Liss, Inc.Key words: CCL17; CCL22; Foxp3; regulatory T cells; gastric cancer It has been reported that regulatory T cells (T regs) play important roles in immunological self-tolerance, 1-4 and are functionally immune-suppressive subsets of T cells. T regs are identified as a small population of CD4 1 cells that constitutively express CD25 (IL-2 receptor a chain) on their surface, and several other markers, including CD45RO, glucocorticoid-induced tumor-necrosis factor receptor-related protein (GITR), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), are also known to be expressed on T regs. [3][4][5] Recently, it has been reported that Foxp3, forkhead/ winged helix transcription factor, is the most reliable marker of T regs 6,7 ; therefore, it is possible to define T regs more strictly as CD4 1 CD25 1 Foxp3 1 cells.In mice, it is known that auto-immune diseases such as ulcerative colitis or Crohn's disease occur due to the depletion of T regs. 6,8 Also in humans, immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is an auto-immune disease developed from a deficiency of T regs. [8][9][10][11] These observations indicate that T regs play important roles in immunological homeostasis. Although the mechanisms of suppression by T regs are still unclear, it has been reported that T regs can inhibit the function of effector T cells directly by cell to cell contact or indirectly via the se...
These results strongly suggest that tumor-related factors induce and expand CD4(+)CD25high T regs.
It has been reported that the population of regulatory T cells (T regs) is increased in tumour-infiltrating lymphocytes in cancer-bearing hosts. Recently, forkhead/winged helix transcription factor p3, Foxp3, is thought to be the most reliable marker of T regs. In the present study, we investigated the prevalence and localisation pattern of Foxp3 þ cells in gastric cancer (n ¼ 80) by immunohistochemistry, in relation to the clinical outcome of gastric cancer patients. Immunohistochemical staining was performed with anti-Foxp3 mAb, and Foxp3 þ cells were semiquantified. We divided all cases into two groups: Foxp3 þ -high (n ¼ 40) and Foxp3 þ -low (n ¼ 40) groups, by the median size of the population of Foxp3 þ cells. Furthermore, in terms of the localisation pattern of accumulating Foxp3 þ cells in tumours, we classified all cases into three groups: a peri-tumour group (n ¼ 30), a diffuse group (n ¼ 40), and a follicular group (n ¼ 10). As a result, although the populations of Foxp3 þ cells in stage IV were significantly larger than those in stage I (Po0.05), there was no significant difference in survival between the patients with high and low population levels of Foxp3 þ cells. However, survival in patients with a diffuse pattern of Foxp3 þ cells was significantly poorer than in those with a peritumoral pattern. In conclusion, the localisation pattern, but not the population size, of Foxp3 þ cells was significantly related to patient survival.
The utilisation of antitumour T cells induced by cancer vaccination with HER-2 peptides or antibodies (Herceptin) against HER-2, as immunotherapy for oesophageal cancer, is a novel and attractive approach. It is important to clarify the frequencies of HER-2 expression and gene amplification in patients with oesophageal squamous cell carcinoma (SCC) and to evaluate the relationship between HER-2 status and HLA haplotype, since the candidates for HER-2 peptide-based vaccination are restricted to a certain HLA haplotype. We determined the frequency of HER-2 expression using the HercepTestt for immunohistochemistry and HER-2 gene amplification by fluorescence in situ hybridisation (FISH) assay in oesophageal SCC (n ¼ 66). HER-2-positive tumours (1 þ /2 þ /3 þ ) analysed by a HercepTest were observed in 30.3% of all the patients and HER-2 gene amplification evaluated by FISH was observed in 11.0% of all the patients, in which all HercepTest (3 þ ) tumours were found to have gene amplification and three of six moderately positive (2 þ ) tumours showed gene amplification. Furthermore, HER-2-positive cells were present more diffusely and were larger within each tumour in the patients who were HercepTest 3 þ than those who were HercepTest 1 þ . Moreover, the survival rate in HER-2-positive group was significantly worse than that in HER-2-negative group. Also, the survival rate in the patients with HER-2 gene amplification was significantly worse than that without HER-2 gene amplification. In addition, oesophageal SCC patients with both HLA-A24-positive and HER-2-positive tumours (1 þ /2 þ /3 þ ) accounted for 26% of these cases, and both HLA-A2-and HER-2-positive tumours accounted for 18% of them.
To evaluate the possibility of treatment with antiepidermal growth factor receptor (EGFR) mAb, Cetuximab against esophageal squamous cell carcinoma (SCC), we performed detail analysis of the antibody‐dependent cellular cytotoxicity (ADCC) mediated by Cetuximab against esophageal SCC. Esophageal SCC cell lines with various levels of EGFR (n = 8) were evaluated for their Cetuximab‐mediated ADCC by 51Cr‐release assay. As a result, Cetuximab was able to induce ADCC against EGFR‐expressing esophageal SCC and the activities reflected the degree of EGFR expression on the esophageal SCC. The activities of Cetuximab‐mediated ADCC by patients' PBMC were impaired in comparison with those by healthy donors' PBMC. Moreover, the inhibition of transforming growth factor (TGF)‐β could enhance Cetuximab‐mediated ADCC against TGF‐β‐producing SCC. In conclusion, Cetuximab was able to induce ADCC against EGFR‐expressing esophageal SCC. Some modalities aiming at enhancing the Cetuximab‐mediated ADCC may be necessary for successful Cetuximab treatment of patients with esophageal SCC. © 2006 Wiley‐Liss, Inc.
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