Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer

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.