Immunometabolic Network Interactions of the Kynurenine Pathway in Cutaneous Malignant Melanoma

Abstract

Dysregulation of the kynurenine pathway has been regarded as a mechanism of tumor immune escape by the enzymatic activity of indoleamine 2, 3 dioxygenase and kynurenine production. However, the immune-modulatory properties of other kynurenine metabolites such as kynurenic acid, 3-hydroxykynurenine, and anthranilic acid are poorly understood. In this study, plasma from patients diagnosed with metastatic cutaneous malignant melanoma (CMM) was obtained before (PRE) and during treatment (TRM) with inhibitors of mitogen-activated protein kinase pathway (MAPKIs). Immuno-oncology related protein profile and kynurenine metabolites were analyzed by proximity extension assay (PEA) and LC/MS-MS, respectively. Correlation network analyses of the data derived from PEA and LC/MS-MS identified a set of proteins that modulate the differentiation of Th1 cells, which is linked to 3-hydroxykynurenine levels. Moreover, MAPKIs treatments are associated with alteration of 3-hydroxykynurenine and 3hydroxyanthranilic acid (3HAA) concentrations and led to higher "CXCL11," and "KLRD1" expression that are involved in T and NK cells activation. These findings imply that the kynurenine pathway is pathologically relevant in patients with CMM.

Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism

“…Kyn is produced by catabolism of the essential amino acid tryptophan (Trp), and high concentrations of Kyn can be found in the plasma of multiple cancer types, such as lymphoma, leukemia, 20 melanoma, 21 lung cancer, 22 pancreatic cancer, 23 colon cancer, 24 and renal cell carcinoma, 25 depending on cancer type and individualized gene expression profile. Referencing the previous study that the pathological Kyn could produce and accumulate to micromoles.…”

Kynurenines as a Novel Target for the Treatment of Malignancies

“…In turn, a phase I clinical trial of EOS200271 showed promising results. It has a tolerable safety profile and significantly inhibits endogenous KYN synthesis, indicating effectiveness and durable clinical benefit in patients with recurrent malignant glioma [ 120 ].…”

“…[ 43 , 44 , 45 , 46 , 47 , 181 ]. Additionally, recent preclinical evidence indicates that the IDO1 inhibitors synergize the effects of tumor immuno- and chemotherapies and help to solve the problem of tumor resistance against them [ 83 , 93 , 105 , 106 , 107 , 108 , 112 , 113 , 119 , 120 , 129 , 132 , 133 , 136 , 137 , 143 , 146 , 151 , 154 , 155 , 156 , 157 , 171 ]. In turn, the discoveries concerning the role of IDO1 in tumor angiogenesis suggest that inhibiting its activity may effectively suppress this process, providing a potentially effective solution in the prevention of tumor development and metastasis.…”

Tryptophan: Its Metabolism along the Kynurenine, Serotonin, and Indole Pathway in Malignant Melanoma

“…Branches in this pathway produce anthranilic acid (AA), xanthurenic acid (XA), and picolinic acid (PIC). The remaining Kyn is converted to a neuroprotective kynurenic acid (KYNA) [ 8 , 9 ]. Changes in the kynurenine pathway are implicated in a variety of neuropsychiatric and neurodegenerative diseases, immunological disorders, and many other disease states.…”

“…Changes in the kynurenine pathway are implicated in a variety of neuropsychiatric and neurodegenerative diseases, immunological disorders, and many other disease states. Recent studies have shown that the kynurenine pathway may be involved in acute and chronic skin damage by UV radiation [ 8 , 10 , 11 ]. IDO, TDO, and L-kynurenine have been shown to accelerate tumorigenesis, proliferation, invasion, and metastasis.…”