The Urothelial Transcriptomic Response to Interferon Gamma: Implications for Bladder Cancer Prognosis and Immunotherapy.
Simon C BakerAndrew S MasonRaphael G SlipPontus ErikssonGottfrid SjödahlLudwik K TrejdosiewiczJennifer SouthgatePublished in: Cancers (2022)
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.
Keyphrases
- immune response
- dendritic cells
- free survival
- single cell
- high grade
- spinal cord injury
- machine learning
- signaling pathway
- urinary tract
- cell cycle
- genome wide
- mesenchymal stem cells
- rna seq
- cell proliferation
- toll like receptor
- transcription factor
- binding protein
- inflammatory response
- cell therapy
- clinical practice
- drug induced
- high speed
- stress induced
- genome wide analysis