Foxp3 + CD4 + CD25 + regulatory T (Treg) cells and immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) play an important role in immunoregulation. Accumulating evidence shows that IDO and Treg cells have potent regulatory properties for immune escape in cancer. To evaluate the expression of IDO and the localization of Foxp3 + Treg cells in the development and progression of uterine cervical cancer, IDO expression and Foxp3 + Treg cells in the primary and metastatic lesions were studied using immunohistochemistry. IDO expression in tumor cells appeared in cervical intraepithelial neoplasia (CIN)-3 of the uterine cervix and marked expression in microinvasive cancer cells was observed. Interestingly, IDO expression in invasive cancer was confined to the cancer cells at the invasive front. Moreover, antigen-presenting cells (APC) at the invasive front in primary and metastatic lesions were also expressing IDO. Stromal Foxp3 + Treg cells appeared in CIN-3 and increased in microinvasive and invasive cancer. Intraepithelial Foxp3 + Treg cells were restricted within microinvasive and invasive cancer. No significant differences in the proportion of Foxp3 + /CD4 + in the stroma or epithelium, or between non-metastatic and metastatic invasive cancers, were observed in primary lesions of cervical cancer, while there was a significant increase (P < 0.005) in the proportion of Foxp3 + /CD4 + in metastatic lymph nodes compared with non-metastatic lymph nodes. Some of the Foxp3 + Treg cells in metastatic lymph nodes contacted the IDO + APC. IDO expression at the invasive front of cancer cells and APC, and the localization of Foxp3 + Treg cells in front of cancer tissues, may create a network between IDO and Treg for the induction of immune escape. (Cancer Sci 2007; 98: 874-881) U terine cervical cancer is considered to be an important immunogenic tumor because human papillomavirus (HPV) causes multistep carcinogenesis (dysplasia-carcinoma in situ-invasive cancer-metastatic cancer) in normal cervical cells. HPV-induced carcinogenesis allows cervical cancer cells to escape immune surveillance, and to achieve the peripheral tolerance of cancer cells. Immune escape is a crucial feature of cancer progression. (1,2) However, the mechanisms by which tolerance is created are still largely unknown. Recent studies suggest that one mechanism contributing to this phenomenon could be tryptophan catabolism, carried out by the immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO). (3-5) IDO is a catalyzing enzyme of tryp-tophan along the kynurenine pathway. (6) The activity of IDO in the mouse placenta has an important role in preventing the rejection of allogenic fetuses. (7) IDO seems to block the proliferation of alloreactive T lymphocytes by the local depletion of tryptophan. T lymphocytes are extremely sensitive to tryptophan shortage, which causes their arrest in the G1 phase of the cell cycle. (8) These observations introduced the concept that IDO expression could suppress immune responses locally by blocking T cells and nat...
The survival period of trastuzumab-treated mice was longer than that of the control group. From these findings, trastuzumab appears to be a candidate as a treatment modality for HER2 overexpressing ovarian CCA.
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