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.
Cancers. 2022 Oct 27*** epublish ***
Simon C Baker, Andrew S Mason, Raphael G Slip, Pontus Eriksson, Gottfrid Sjödahl, Ludwik K Trejdosiewicz, Jennifer Southgate
Jack Birch Unit of Molecular Carcinogenesis, Department of Biology and York Biomedical Research Institute, University of York, Heslington, York YO10 5DD, UK., Division of Oncology, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden., Department of Translational Medicine, Lund University, 20502 Malmö, Sweden.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/36358715