Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion

Abstract

Background: Indoleamine 2,3-dioxygenase (IDO), the first step in the kynurenine pathway (KP), is upregulated in some cancers and represents an attractive therapeutic target given its role in tumour immune evasion. However, the recent failure of an IDO inhibitor in a late phase trial raises questions about this strategy. Methods: Matched renal cell carcinoma (RCC) and normal kidney tissues were subject to proteomic profiling. Tissue immunohistochemistry and gene expression data were used to validate findings. Phenotypic effects of loss/gain of expression were examined in vitro. Results: Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being down-regulated in RCC. Loss of QPRT expression led to increased potential for anchorage-independent growth. Gene expression, mass spectrometry (clear cell and chromophobe RCC) and tissue immunohistochemistry (clear cell, papillary and chromophobe), confirmed loss or decreased expression of QPRT, and showed down-regulation of other KP enzymes including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or up-regulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway. Conclusions: Widespread dysregulation of the KP is common in RCC and is likely to contribute to tumour immune evasion, carrying implications for effective therapeutic targeting of this critical pathway

WITHDRAWN: Establishment and validation of a novel metabolism-related genesignature for predicting overall survival of patients with breast cancer

“…The overexpression of DCTPP1 and QPRT is related to the slow progress of BC, which promotes the growth, migration and invasion of MCF7 and T47D cells, but inhibits cell apoptosis DSCAM-AS1 gene knockout reduced the expression of DCTPP1 and QPRT, and inhibited the growth, migration and invasion of estrogen receptor-positive BC (40). Phosphoribosyl transferase (QPRT) is the terminal rate-limiting enzyme in KP Kynurenine pathway ,and its expression is down-regulated, Widespread dysregulation of KP in renal cell carcinoma is common and may lead to tumor immune escape, which is of great signi cance for effective targeted therapy of this key pathway (41).…”

Kynurenine pathway in kidney diseases

“…Moreover, serum KYN was significantly elevated in RCC patients, whereas the KYN/Trp ratio was linked to clinical stage, tumour size, Fuhrman grade, lymph node involvement and visceral metastases. More evidence about enzymatic dysregulation of the KYN pathway in RCC was provided by Hornigold et al [ 106 ]. In contrast to IDO upregulation, a decrease in quinolinic acid phosphoribosyltransferase (QPRT) and HAAO expression was detected.…”

Quinolinate Phosphoribosyltransferase Promotes Invasiveness of Breast Cancer Through Myosin Light Chain Phosphorylation

“…Increased QPRT expression was observed in glioblastomas and follicular thyroid carcinomas ( 12 , 33 ). Conversely, QPRT expression was decreased in renal cell carcinoma in comparison to normal kidney tissue ( 34 ). Furthermore, QPRT expression was decreased in metastatic melanoma after the acquisition of resistance to BRAF inhibitors ( 35 ).…”