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

• Published in: Cancers Vol. 14; no. 21; p. 5295
• Main Authors: Baker, Simon C., Mason, Andrew S., Slip, Raphael G., Eriksson, Pontus, Sjödahl, Gottfrid, Trejdosiewicz, Ludwik K., Southgate, Jennifer
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 27.10.2022; MDPI
• Subjects: Antigens; BCG; Bladder cancer; Cancer; Cancer and Oncology; Cancer och onkologi; Care and treatment; Cell culture; Chemokines; Clinical Medicine; Development and progression; Epithelial cells; Gene expression; Health aspects; Immune checkpoint; Immunotherapy; Inflammation; Interferon gamma; Invasiveness; Klinisk medicin; Lymphocytes T; Major histocompatibility complex; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Methods; PD-L1; PD-L1 protein; Regression analysis; RNA; Survival analysis; Transcriptomics; Tumors; Urinary tract; Urothelium; VISTA; γ-Interferon; United Kingdom; United Kingdom > UK
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14215295

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.