Abstract
Immune escape and acquisition of tolerance by tumor cells are essential to cancer growth and progression. Therefore, considerable attention has been paid to overcoming the immune resistance of tumors as a novel strategy for cancer therapy. This review focuses on the tryptophan-catabolizing and immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO), and its functional role in gynecologic cancers, such as endometrial cancer, ovarian cancer, cervical cancer, and vulvar cancer. IDO induces tolerance to the host immune surveillance through suppressing the proliferation of effector T-cells or natural killer cells and their killer functions within the tumor microenvironment. In gynecologic cancers, IDO is highly expressed in more than half of cases, and tumoral IDO expression is correlated with advanced surgical stage and impaired patient survival. In preclinical studies in mice, an IDO inhibitor 1-methyltryptophan suppresses tumor growth and peritoneal dissemination, and increases the efficacy of chemotherapeutic agents. In summary, IDO is a novel prognostic indicator for endometrial, ovarian, cervical, and vulvar cancers. IDO inhibition may be a promising strategy to restore host anti-tumor immunity and to enhance the anti-tumor potential of current chemotherapy, radiotherapy, and immunotherapy for gynecologic cancers.
Highlights
Gynecologic cancer mainly consists of three major tumors; endometrial carcinoma, ovarian carcinoma, and uterine cervical carcinoma, and includes vulvar carcinoma
CD4+CD25+ Foxp3+ regulatory T (Treg) cells, directly activating mature Tregs [22,23]. These findings suggest that IDO, in cooperation with Treg, induces the immune tolerogenic microenvironment, which leads to tumor progression (Figure 1)
These findings suggest that IDO expression is associated with poor clinical outcome via suppression of tumor-infiltrating lymphocytes (TIL) and/or natural killer (NK) cells within the tumor microenvironment
Summary
Gynecologic cancer mainly consists of three major tumors; endometrial carcinoma, ovarian carcinoma, and uterine cervical carcinoma, and includes vulvar carcinoma. Subsequent studies have shown that IDO expression is correlated with disease progression or poor clinical outcomes in various histologic cancer types [24]. In gynecologic cancers including endometrial, ovarian, cervical, and vulvar carcinomas, associations of IDO expression with tumor progression or clinical outcomes have been extensively studied by the authors and others.
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