Investigating the Role of Indoleamine 2,3-dioxygenase (IDO) in Breast Cancer Metastasis

摘要

Indoleamine 2,3-dioxygenase (IDO1) is a tryptophan catabolizing enzyme known to support primary tumor outgrowth through immune suppression though there is little data addressing its role in metastasis, an important aspect of tumor malignancy. Tumors formed by orthotopic engraftment of the malignant 4T1 breast carcinoma cell line exhibit metastatic spread to organs similar to that seen in human breast cancer with pulmonary metastases being the primary cause of mortality in this model. To determine the role of IDO1 in breast cancer metastasis, we have utilized IDO1 knockout (IDO1-/-) mice to directly study the impact of IDO1 loss in the host. While primary tumors in IDO1-/- mice exhibited a similar growth rate to that observed in the wild-type (WT) control, survival was significantly increased in the IDO1-/- mice. Further analysis of IDO1-/- mice showed approximately 10-fold less metastatic burden in the lungs of these mice. Serum isolated from IDO1-/- and WT controls showed similar levels of metastatic cells indicating that the reduced metastatic spread is not due to decreased tumor cell migration but rather to the reduced ability to establish tumor metastases. Evaluation of the tumor microenvironment showed that IDO1 protein and activity in WT mice directly correlate to metastatic burden. Higher levels of MCP1 and IL6 were observed in WT mice compared to IDO1-/-. The immune cell profile in these two populations also differs, leading us to conclude that IDO1 expression in normal lung tissue influences the immune response and supports the development of metastases.