Abstract
Tumorigenesis is a complex multifactorial and multistep process in which tumors can utilize a diverse repertoire of immunosuppressive mechanisms to evade host immune attacks. The degradation of tryptophan into immunosuppressive kynurenine is considered an important immunosuppressive mechanism in the tumor microenvironment. There are three enzymes, namely, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2), involved in the metabolism of tryptophan. IDO1 has a wider distribution and higher activity in catalyzing tryptophan than the other two; therefore, it has been studied most extensively. IDO1 is a cytosolic monomeric, heme-containing enzyme, which is now considered an authentic immune regulator and represents one of the promising drug targets for tumor immunotherapy. Collectively, this review highlights the regulation of IDO1 gene expression and the ambivalent mechanisms of IDO1 on the antitumoral immune response. Further, new therapeutic targets via the regulation of IDO1 are discussed. A comprehensive analysis of the expression and biological function of IDO1 can help us to understand the therapeutic strategies of the inhibitors targeting IDO1 in malignant tumors.
Highlights
Tryptophan (Trp) depletion and kynurenine (Kyn) production promote immunosuppression in different tumor types [1, 2]
In most cancers, such as glioblastomas, melanomas, colon carcinomas, lung carcinomas, and endometrium carcinomas, TDO could be detected in pericytes that belonged to morphologically abnormal vessels in the intratumoral rather than tumor cells themselves [62], the mechanism that triggers TDO expression in tumor pericytes and the relationship between TDO-expression pericytes and abnormal vessels are all unclear, which suggests that TDO may play a proangiogenic role depending on its expression site in certain cancer types
GCN2 does not mediate suppression of antitumor T-cell responses by Trp catabolism in experimental melanomas [78], and GCN2 is required for normal cytotoxic Tcell function [79], which suggests that the immune regulatory role of GCN2 in subsets of T cells may depend on the complex context in different types of tumors
Summary
Tryptophan (Trp) depletion and kynurenine (Kyn) production promote immunosuppression in different tumor types [1, 2]. The recent studies revealed that TDO could be involved in modulating antitumor immune responses and the antitumor immunotherapy efficacy [60, 61], but it did not colocalize with IDO1, at least, in human glioblastoma [62] In most cancers, such as glioblastomas, melanomas, colon carcinomas, lung carcinomas, and endometrium carcinomas, TDO could be detected in pericytes that belonged to morphologically abnormal vessels in the intratumoral rather than tumor cells themselves [62], the mechanism that triggers TDO expression in tumor pericytes and the relationship between TDO-expression pericytes and abnormal vessels are all unclear, which suggests that TDO may play a proangiogenic role depending on its expression site in certain cancer types. GCN2 does not mediate suppression of antitumor T-cell responses by Trp catabolism in experimental melanomas [78], and GCN2 is required for normal cytotoxic Tcell function [79], which suggests that the immune regulatory role of GCN2 in subsets of T cells may depend on the complex context in different types of tumors. Certain IDO1 inhibitors unexpectedly impair NK cell-mediated killing in tumors, which suggests that we consider the inhibitory mechanisms of different IDO1 inhibitors and their effects on others cells, especially immune cells
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