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.
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.
Quinolate phosphoribosyltransferase (QPRT), the final and rate-limiting enzyme in the KP, was identified as being downregulated 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 downregulation of other KP enzymes, including kynurenine 3-monoxygenase (KMO) and 3-hydroxyanthranilate-3,4-dioxygenase (HAAO), with a concomitant maintenance or upregulation of nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the NAD+ salvage pathway.
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
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We are grateful to the patients for donating samples and the staff of the Leeds Biobanking and Sample Processing Lab and Leeds Multidisciplinary RTB for samples and Anke Bruning-Richardson for technical support with the TMA. We thank the staff of the oncology and urology departments of Leeds Teaching Hospitals NHS Trust who assisted in patient recruitment, Professor W Kaelin for the 786-VHL cell lines, Robert Schwarz for providing antibody to QPRT, Darren Tomlinson for providing the parental QPRT vector, Anthea Stanley for laboratory support and Nick Totty and Sarah Hanrahan for the sequencing of the 2D-PAGE proteins.
Ethics approval and consent to participate
The study was approved by the Leeds East Research Ethics Committee (ethical approval 15/YH/0080) and performed in accordance with the Declaration of Helsinki. All samples were obtained with the patients’ informed consent.
Consent for publication
No individually identifiable data are presented.
RNA-seq data, generated through our ICGC CAGEKID study, has been deposited in a public repository as described elsewhere: Scelo et al.30 Proteomic data sets are available on request.
A.H. is Editor-in-Chief of British Journal of Cancer. R.S.’s current role is Publishing Editor for British Journal of Cancer.
This work was supported by funding from the University of Leeds and Cancer Research UK. E.R.M. is funded by the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre) and Cancer Research UK Cambridge Cancer Centre. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. The University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve.
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Hornigold, N., Dunn, K.R., Craven, R.A. et al. Dysregulation at multiple points of the kynurenine pathway is a ubiquitous feature of renal cancer: implications for tumour immune evasion. Br J Cancer 123, 137–147 (2020). https://doi.org/10.1038/s41416-020-0874-y
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