Abstract
Metabolism of tryptophan (Trp), an essential amino acid, represent a major metabolic pathway that both promotes tumor cell intrinsic malignant properties as well as restricts antitumour immunity, thus emerging as a drug development target for cancer immunotherapy. Three cytosolic enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO2), catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression mainly through the aryl hydrocarbon receptor (AhR) activation in numerous types of cancer. By restoring antitumor immune responses and synergizing with other immunotherapies, the encouraging preclinical data of IDO1 inhibitors has dramatically failed to translate into clinical success when combined with immune checkpoints inhibitors, reigniting the debate of combinatorial approach. In this review, we i) provide comprehensive evidences on immunomodulatory role of the Trp catabolism metabolites that highlight this pathway as relevant target in immuno-oncology, ii)ii) discuss underwhelming results from clinical trials investigating efficacy of IDO1 inhibitors and underlying mechanisms that might have contributed to this failure, and finally, iii) discuss the current state-of-art surrounding alternative approaches of innovative antitumor immunotherapies that target molecules of Trp catabolism as well as challenges and perspectives in the era of immunotherapy.
Highlights
Over the last decade, tumor immune escape has been envisioned as a new paradigm that contributes to tumor growth and evasion, appearing as an attractive therapeutic strategy [1]
The broad clinical use of immune checkpoint inhibitors (ICIs) highlights the success in struggling cancer by enhancing T cell-mediated adaptative antitumor immune response
We provide updated informations on recent advances in the development of innovative anticancer immunotherapies targeting the Trp catabolism and discuss upon the current challenges and future perspectives in the field of immuno-oncology
Summary
Tumor immune escape has been envisioned as a new paradigm that contributes to tumor growth and evasion, appearing as an attractive therapeutic strategy [1] In this regard, new advances in immunotherapies with immune checkpoint inhibitors (ICIs), including drugs targeting the programmed death receptor 1 (PD-1) or its ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4), has revolutionized the oncology field and afforded patients with various types of cancer the potential for long-term survival [2]. Anticancer therapies (such as chemotherapy, radiotherapy, and targeted therapy) therapeutically act by direct elimination of proliferating cancer cells. Their efficacy has been hindered by limiting. The broad clinical use of ICIs highlights the success in struggling cancer by enhancing T cell-mediated adaptative antitumor immune response
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