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

May 12, 2020

Contributor: Nick Hornigold,Karen R Dunn,Rachel A Craven,Alexandre Zougman,Sebastian Trainor,Rebecca Shreeve,Joanne Brown,Helen Sewell,Michael Shires,Margaret Knowles,Tsutomu Fukuwatari,Eamonn R Maher,Julie Burns,Selina Bhattarai,Mini Menon,Alvis Brazma,Ghislaine Scelo,Lara Feulner,Yasser Riazalhosseini,Mark Lathrop,Adrian Harris,Peter J Selby,Rosamonde E Banks,Naveen S Vasudev

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

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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About The Expert

Nick Hornigold

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Karen R Dunn

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Rachel A Craven

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Alexandre Zougman

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Leeds Institute of Medical Research at St James’s, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Sebastian Trainor

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Rebecca Shreeve

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Joanne Brown

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Leeds Institute of Medical Research at St James’s, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Helen Sewell

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Michael Shires

Leeds Institute of Medical Research at St James’s, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Margaret Knowles

Molecular Genetics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Tsutomu Fukuwatari

Department of Nutrition, The University of Shiga Prefecture, 2500 Hassaka, Hikone, 5228533, Japan.

Eamonn R Maher

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.

Julie Burns

Molecular Genetics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Selina Bhattarai

Department of Pathology, St James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Mini Menon

Department of Pathology, St James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Alvis Brazma

European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK.

Ghislaine Scelo

International Agency for Research on Cancer (IARC), Genetic Epidemiology Group, 150 cours Albert Thomas, 69372, Lyon, France.

Lara Feulner

McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.

Yasser Riazalhosseini

McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.

Mark Lathrop

McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.

Adrian Harris

Cancer Research UK Clinical Centre, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.

Peter J Selby

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Rosamonde E Banks

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Leeds Institute of Medical Research at St James’s, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK.

Naveen S Vasudev

Clinical and Biomedical Proteomics Group, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK. n.vasudev@leeds.ac.uk.

Leeds Institute of Medical Research at St James’s, University of Leeds, St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK. n.vasudev@leeds.ac.uk.

References

PubMed