The amino acid Tryptophan is catabolized in our body primarily through the kynurenine pathway, which is initiated by the enzymes - indoleamine 2,3-dioxygenases (IDO)-1 and IDO-,2 and by the structurally distinct tryptophan dioxygenase, TDO. Their metabolic functions can modulate infection via suppression of pathogen replication (e.g. during toxoplasmosis or chlamydial infections) or by limiting the expansion of viral infection. However, several studies have also uncovered the roles of these enzymes in inflammatory programming and in acquired immune tolerance via the effects of tryptophan metabolites on T-cell mediated immunity.
In recent years, accumulating evidence has indicated that IDO and TDO have important immuno-modulatory roles in cancer. IDO1, which is the most studied among this class of enzymes, is widely expressed in tumor cells, immune cells, as well as in stromal cells of the tumor microenvironment. Moreover, IDO1 has been established as a driver of immune escape, vasculogenesis and metastasis in cancer. In addition, IDO1 expression in the tumor microenvironment or in the blood has been associated with poor patient prognosis. Several findings indicate that increased kyn/trp ratio in the blood of patients with lung cancer and melanoma, reflecting increased IDO activity, is associated with worsened patient outcome .
Given the important roles of the IDO pathway in regulating anti-tumor immune responses, there has been increasing interest in targeting IDO therapeutically in order to treat cancer. In early phase clinical trials for melanoma, head and neck cancer and several other solid cancers, several IDO1 inhibitors such as indoximod, epacadostat and an IDO peptide vaccine have shown promising results as a combination strategy together with chemotherapy and/or immunotherapy. Although a recent phase 3 trial with anti-PD1 immunotherapy in combination with IDO1 inhibition was unsuccessful (ECHO 301), concerns about the design of this trial have been raised and other clinical trials involving such combinatorial strategies continue to be explored. Beyond IDO1, growing attention is being paid to TDO and IDO2 based on their co-expression with IDO1 in many tumors or tumoral antigen-presenting cells, respectively. Extensive translational data supports on-going studies on the application of IDO1 inhibitors and next generation combi-pan IDO/TDO inhibitors as an immune-metabolic strategy to safely leverage the efficacy of cancer immunotherapy and other types of cancer treatment.
In this Research Topic, we welcome the submission of Original Research, Methods, Clinical Trials and Case Reports covering the following topics:
1. Effect of IDO / TDO on innate and adaptive immune pathways during cancer.
2. Role of IDO / TDO in tumor cells, immune cells as well as the cells of the tumor microenvironment.
3. Roles of IDO/TDO as biomarkers in cancer.
4. Application of IDO1 inhibitors in cancer treatment from an immunological perspective.
Topic Editor Dr. Alexander J. Muller receives financial support by IO Biotech company. All other Topic Editors declare no competing interests with regards to the Research Topic subject.
The amino acid Tryptophan is catabolized in our body primarily through the kynurenine pathway, which is initiated by the enzymes - indoleamine 2,3-dioxygenases (IDO)-1 and IDO-,2 and by the structurally distinct tryptophan dioxygenase, TDO. Their metabolic functions can modulate infection via suppression of pathogen replication (e.g. during toxoplasmosis or chlamydial infections) or by limiting the expansion of viral infection. However, several studies have also uncovered the roles of these enzymes in inflammatory programming and in acquired immune tolerance via the effects of tryptophan metabolites on T-cell mediated immunity.
In recent years, accumulating evidence has indicated that IDO and TDO have important immuno-modulatory roles in cancer. IDO1, which is the most studied among this class of enzymes, is widely expressed in tumor cells, immune cells, as well as in stromal cells of the tumor microenvironment. Moreover, IDO1 has been established as a driver of immune escape, vasculogenesis and metastasis in cancer. In addition, IDO1 expression in the tumor microenvironment or in the blood has been associated with poor patient prognosis. Several findings indicate that increased kyn/trp ratio in the blood of patients with lung cancer and melanoma, reflecting increased IDO activity, is associated with worsened patient outcome .
Given the important roles of the IDO pathway in regulating anti-tumor immune responses, there has been increasing interest in targeting IDO therapeutically in order to treat cancer. In early phase clinical trials for melanoma, head and neck cancer and several other solid cancers, several IDO1 inhibitors such as indoximod, epacadostat and an IDO peptide vaccine have shown promising results as a combination strategy together with chemotherapy and/or immunotherapy. Although a recent phase 3 trial with anti-PD1 immunotherapy in combination with IDO1 inhibition was unsuccessful (ECHO 301), concerns about the design of this trial have been raised and other clinical trials involving such combinatorial strategies continue to be explored. Beyond IDO1, growing attention is being paid to TDO and IDO2 based on their co-expression with IDO1 in many tumors or tumoral antigen-presenting cells, respectively. Extensive translational data supports on-going studies on the application of IDO1 inhibitors and next generation combi-pan IDO/TDO inhibitors as an immune-metabolic strategy to safely leverage the efficacy of cancer immunotherapy and other types of cancer treatment.
In this Research Topic, we welcome the submission of Original Research, Methods, Clinical Trials and Case Reports covering the following topics:
1. Effect of IDO / TDO on innate and adaptive immune pathways during cancer.
2. Role of IDO / TDO in tumor cells, immune cells as well as the cells of the tumor microenvironment.
3. Roles of IDO/TDO as biomarkers in cancer.
4. Application of IDO1 inhibitors in cancer treatment from an immunological perspective.
Topic Editor Dr. Alexander J. Muller receives financial support by IO Biotech company. All other Topic Editors declare no competing interests with regards to the Research Topic subject.
