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.
Highlights
Cutaneous malignant melanoma (CMM) is the most common form of melanomas and arises from a malignant transformation of melanocytes [1]
To gain further insight into mutations, copy-number alterations, and expression profiles of Kynurenine pathway (KP) enzymes, we examined the TCGA database
We found that genetic alterations of KATs that mediate kynurenic acid (KYNA) production from KYN were associated with a reduced survival rate in melanoma patients in the TCGA cohort (Figure 1D)
Summary
Cutaneous malignant melanoma (CMM) is the most common form of melanomas and arises from a malignant transformation of melanocytes [1]. The 5-year relative survival rate for patients with stage I CMM is more than 95%, while until recently, median survival was only 6–9 months in stage IV disease [1]. Targeting the oncogenic mitogen-activated protein kinase (MAPK) pathway with small molecule inhibitors, i.e., BRAF and/or MEK inhibitors (MAPK-inhibitors; MAPKIs), Immunometabolic Network of the Kynurenine Pathway has led to improved overall survival (OS) and progression-free survival (PFS) in patients with BRAF-mutant CMM [2]. It has been shown that patients with advanced CMM receiving immune checkpoint inhibitors (ICPIs), targeting the immunosuppressive programmed cell death 1 receptor (PD-1) have favorable response rate (33–44%). Preliminary results in patients with metastatic melanoma indicate that combining indolamine 2, 3-dioxygenase 1 inhibitors (IDO1i) with either CTLA-4 inhibitor or PD-1 inhibitor (PD-1i) increases the effectiveness of these immunotherapies in CMM patients [7,8,9]. In (ECHO-301/Keynote252), randomized controlled trial in patients with metastatic melanoma, combination treatment with an IDO1 inhibitor, epacadostat, and the PD-1i, pembrolizumab, did not show any improvement of survival compared to single therapy with PD-1i [10]
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