Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner.

The transcription factor Foxp3 plays a key role in CD4(+)CD25(+) regulatory T (Treg) cell function. A correlation has been shown between survival and the frequency of tumor-infiltrating Foxp3-positive Treg cells in cancer patients. However, few studies have characterized the regulation of Foxp3 expression and function in Treg cells, which are known to comprise distinct subsets, with different roles in the complex tumor microenvironment. Here, we show that significantly more Foxp3-positive Treg cells accumulated in gastric tumors. In addition, we found increased expression of Foxp3 protein per cell in tumor-infiltrating Treg cells. Moreover, elevated Foxp3 expression in tumor-infiltrating Treg cells was associated with the TNM stage in gastric cancer patients. Importantly, further investigation within the tumor microenvironment showed that expression of Foxp3 in Treg cells correlated with expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)). Furthermore, Treg cells with higher levels of Foxp3 were able to suppress the proliferation of autologous CD4(+)CD25(-) T cells. The suppression of the effector T-cell response was reversed by COX inhibitors and PGE(2) receptor-specific antagonists. Our data demonstrate a mechanism by which tumor-infiltrating Treg cells with increased Foxp3 expression can mediate immune suppression via COX-2/PGE(2) production in the gastric cancer microenvironment. Thus, we provide new insights into overcoming regulatory T-cell activity, which may be beneficial for the treatment of human gastric cancer.

Yuan XL ，Chen L ，Li MX ，Dong P ，Xue J ，Wang J ，Zhang TT ，Wang XA ，Zhang FM ，Ge HL ，Shen LS ，Xu D ... -  《-》

CD4(+)CD25(+)CD127(low/-) regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression.

Shen LS ，Wang J ，Shen DF ，Yuan XL ，Dong P ，Li MX ，Xue J ，Zhang FM ，Ge HL ，Xu D ... -  《-》

Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.

Sharma S ，Yang SC ，Zhu L ，Reckamp K ，Gardner B ，Baratelli F ，Huang M ，Batra RK ，Dubinett SM ... -  《CANCER RESEARCH》

CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer.

Kiniwa Y ，Miyahara Y ，Wang HY ，Peng W ，Peng G ，Wheeler TM ，Thompson TC ，Old LJ ，Wang RF ... -  《CLINICAL CANCER RESEARCH》

Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients.

Fu J ，Xu D ，Liu Z ，Shi M ，Zhao P ，Fu B ，Zhang Z ，Yang H ，Zhang H ，Zhou C ，Yao J ，Jin L ，Wang H ，Yang Y ，Fu YX ，Wang FS ... -  《GASTROENTEROLOGY》