Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer.
ABSTRACT Although Th17 cells reportedly play critical roles in the development of autoimmunity and allergic reactions, information on Th17 cells in cancer-bearing hosts is still limited. In the present study, we investigated the distribution of Th17 cells in relation to regulatory T cells (Treg) in the tumor-infiltrating lymphocytes (TILs), regional lymph node lymphocytes, and peripheral blood lymphocytes of gastric cancer patients. Interleukin (IL)-17-producing CD4(+) cells as Th17 cells and CD4(+)CD25(+)FoxP3(+) cells as Treg were evaluated by flow cytometry and expressed as a percentage of the total CD4(+) cells, in addition to performing a Th1/Th2 balance assay. Moreover, immunohistochemical staining for IL-17 and FoxP3 were performed. In TILs from patients with early disease (n = 27), the frequency of Th17 cells was significantly higher than that in the normal gastric mucosa (23.7 ± 8.9 vs 4.5 ± 3.1%). In TILs from patients with advanced disease (n = 28), the frequency of Th17 cells was also significantly higher, but lower compared to early disease, than that in the normal gastric mucosa (15.1 ± 6.2 vs 4.0 ± 2.0%). This observation for Th17 cell-distribution was also confirmed by immunohistochemistry. When the ratio of Th17/Treg in TILs was evaluated in individual cases, it was more markedly increased in early than in advanced disease. In conclusion, the accumulation of Th17 cells as well as Treg in the tumor microenvironment of gastric cancer occurred in early disease and then the infiltration of Th17 cells gradually decreased according to the disease progression, in contrast to increased Treg.
Article: Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions.[show abstract] [hide abstract]
ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mTOR complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type II diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and -independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression.Cancer Prevention Research 04/2012; 5(4):562-73. · 4.91 Impact Factor
Article: Persistent Helicobacter pylori specific Th17 responses in patients with past H. pylori infection are associated with elevated gastric mucosal IL-1β.[show abstract] [hide abstract]
ABSTRACT: Ongoing Helicobacter pylori (HP) infection triggers a chronic active gastritis. Eradicating HP reduces gastric inflammation, but does not eliminate it. We sought to characterize this persistent gastritis, and demonstrate the persistence of HP-specific Th17 responses in individuals previously infected with HP but who no longer had evidence of ongoing infection. Study subjects were divided into 3 groups 55 individuals had active HP infection (group A), 41 were diagnosed with previous HP infection (group P), and 59 were naïve to HP (group N). Blood and gastric tissue were obtained with written informed consent from all subjects, and immune responses were evaluated using flow cytometry, semi-quantitative real time PCR, immunofluorescent staining, ELISA, and multiplex cytometric bead array for cytokine quantification. Elevated IL-17A responses were observed in patients from group A compared to group N. Interestingly, IL-17A responses remained persistently elevated in the blood and gastric mucosa of individuals from group P, despite the absence of ongoing HP infection. Using purified CD4(+) T cells as effectors and antibodies that blocked antigen presentation by MHC Class II, we showed that these persistent IL-17A responses were mediated primarily by HP-specific Th17 cells, rather than other immune cells that have also been described to secrete IL-17A. Gastric mucosal IL-1β levels were also persistently elevated in group P, and neutralisation of IL-1β reduced the HP-specific IL-17A response of purified CD4(+) T cells to autologous HP-pulsed antigen presenting cells in vitro, suggesting a functional association between IL-1β and the persistent Th17 response in group P patients. Despite lack of ongoing HP infection, HP-specific Th17 cells persist in the blood and gastric mucosa of individuals with past HP infection. We speculate that this persistent inflammation might contribute to gastric mucosal pathology, for example, persistent increased gastric cancer risk despite eradication of HP.PLoS ONE 01/2012; 7(6):e39199. · 4.09 Impact Factor
Article: Intratumoral expression of IL-17 and its prognostic role in gastric adenocarcinoma patients.[show abstract] [hide abstract]
ABSTRACT: In this study, we characterized the intratumoral expression of IL-17 and CD8(+) TILs in gastric adenocarcinoma patients after resection and determined the correlation between the survival probability of gastric adenocarcinoma patients and the expression of IL-17 in tumor. Expression of IL-17 and CD8 was assessed by immunohistochemistry, and the prognostic effects of intratumoral IL-17 expression and CD8(+) TILs were evaluated by Cox regression and Kaplan-Meier analysis. Immunohistochemical detection revealed the presence of IL-17 and CD8(+) cells in gastric adenocarcinoma tissue samples (90.6%, 174 out of 192 patients and 96.9%, 186 out of 192 patients, respectively). We have also found that intratumoral IL-17 expression was significantly correlated with age (p=0.004) and that the number of CD8(+)TILs was significantly correlated with UICC staging (p=0.012) and the depth of tumor invasion (p=0.022). The five-year overall survival probability among patients intratumorally expressing higher levels of IL-17 was significantly better than those expressing lower levels of IL-17 (p=0.036). Multivariate Cox proportional hazard analyses revealed that intratumoral IL-17 expression (HR: 0.521; 95% CI: 0.329-0.823; p=0.005) was an independent factor affecting the five-year overall survival probability. We conclude that low levels of intratumoral IL-17 expression may indicate poor prognosis in gastric adenocarcinoma patients.International journal of biological sciences 01/2011; 7(1):53-60. · 2.70 Impact Factor