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The Urothelial Transcriptomic Response to Interferon Gamma : Implications for Bladder Cancer Prognosis and Immunotherapy

Baker, Simon C. ; Mason, Andrew S. ; Slip, Raphael G. ; Eriksson, Pontus LU ; Sjödahl, Gottfrid LU ; Trejdosiewicz, Ludwik K. and Southgate, Jennifer (2022) In Cancers 14(21).
Abstract

Interferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory “checkpoint” receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines. Normal urothelium constitutively expressed immunoinhibitory B7 family member VSIR (VISTA), while CD274 (PD-L1) expression was induced/upregulated by IFNγ. We generated a urothelial IFNγ response gene signature. When applied to the... (More)

Interferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory “checkpoint” receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines. Normal urothelium constitutively expressed immunoinhibitory B7 family member VSIR (VISTA), while CD274 (PD-L1) expression was induced/upregulated by IFNγ. We generated a urothelial IFNγ response gene signature. When applied to the unsupervised clustering of non-muscle-invasive bladder cancers, the IFNγ-signature predicted longer recurrence-free survival. In muscle-invasive cancers, the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak or absent. This study offers novel insights into strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BCG, bladder cancer, immune checkpoint, immunotherapy, interferon gamma, PD-L1, urothelium, VISTA
in
Cancers
volume
14
issue
21
article number
5295
publisher
MDPI AG
external identifiers
  • pmid:36358715
  • scopus:85141689808
ISSN
2072-6694
DOI
10.3390/cancers14215295
language
English
LU publication?
yes
id
66025e33-a679-41c7-80e4-766159c0f810
date added to LUP
2022-11-30 10:18:29
date last changed
2024-04-16 14:24:59
@article{66025e33-a679-41c7-80e4-766159c0f810,
  abstract     = {{<p>Interferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory “checkpoint” receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines. Normal urothelium constitutively expressed immunoinhibitory B7 family member VSIR (VISTA), while CD274 (PD-L1) expression was induced/upregulated by IFNγ. We generated a urothelial IFNγ response gene signature. When applied to the unsupervised clustering of non-muscle-invasive bladder cancers, the IFNγ-signature predicted longer recurrence-free survival. In muscle-invasive cancers, the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak or absent. This study offers novel insights into strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.</p>}},
  author       = {{Baker, Simon C. and Mason, Andrew S. and Slip, Raphael G. and Eriksson, Pontus and Sjödahl, Gottfrid and Trejdosiewicz, Ludwik K. and Southgate, Jennifer}},
  issn         = {{2072-6694}},
  keywords     = {{BCG; bladder cancer; immune checkpoint; immunotherapy; interferon gamma; PD-L1; urothelium; VISTA}},
  language     = {{eng}},
  number       = {{21}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{The Urothelial Transcriptomic Response to Interferon Gamma : Implications for Bladder Cancer Prognosis and Immunotherapy}},
  url          = {{http://dx.doi.org/10.3390/cancers14215295}},
  doi          = {{10.3390/cancers14215295}},
  volume       = {{14}},
  year         = {{2022}},
}