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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Nov 11

PMID 36358715

Authors

Simon C Baker

Andrew S Mason

Raphael G Slip

Pontus Eriksson

Gottfrid Sjodahl

Ludwik K Trejdosiewicz

Jennifer Southgate

Affiliations

Soon will be listed here.

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 (VISTA), while (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.

Citing Articles

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells.

Li A, Park S, Li P, Zhou C, Kluz T, Li J Int J Mol Sci. 2024; 25(3).

PMID: 38339062 PMC: 10855786. DOI: 10.3390/ijms25031783.

BCG as an Innovative Option for HCC Treatment: Repurposing and Mechanistic Insights.

Vaziri F, Setayesh T, Hu Y, Ravindran R, Wei D, Wan Y Adv Sci (Weinh). 2024; 11(14):e2308242.

PMID: 38308164 PMC: 11005731. DOI: 10.1002/advs.202308242.

Pembrolizumab plus enfortumab vedotin in urothelial cancer.

Santoni M, Takeshita H, Massari F, Bamias A, Cerbone L, Fiala O Nat Rev Urol. 2024; 21(7):387-388.

PMID: 38267716 DOI: 10.1038/s41585-024-00858-y.

Current Landscape of Immune Checkpoint Inhibitors for Metastatic Urothelial Carcinoma: Is There a Role for Additional T-Cell Blockade?.

Ogbuji V, Paster I, Recio-Boiles A, Carew J, Nawrocki S, Chipollini J Cancers (Basel). 2024; 16(1).

PMID: 38201559 PMC: 10778285. DOI: 10.3390/cancers16010131.

Immune inactivation by VISTA predicts clinical outcome and therapeutic benefit in muscle-invasive bladder cancer.

Li W, Liu Z, Jin K, Shao F, Zeng H, Wang Y BMC Cancer. 2023; 23(1):661.

PMID: 37452272 PMC: 10347783. DOI: 10.1186/s12885-023-11157-x.

References

Lindskrog S, Prip F, Lamy P, Taber A, Groeneveld C, Birkenkamp-Demtroder K . An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat Commun. 2021; 12(1):2301. PMC: 8052448. DOI: 10.1038/s41467-021-22465-w. View

Prescott S, JAMES K, Hargreave T, Chisholm G, Smyth J . Radio-immunoassay detection of interferon-gamma in urine after intravesical Evans BCG therapy. J Urol. 1990; 144(5):1248-51. DOI: 10.1016/s0022-5347(17)39713-6. View

Sjodahl G, Eriksson P, Liedberg F, Hoglund M . Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J Pathol. 2017; 242(1):113-125. PMC: 5413843. DOI: 10.1002/path.4886. View

Cross W, Eardley I, Leese H, Southgate J . A biomimetic tissue from cultured normal human urothelial cells: analysis of physiological function. Am J Physiol Renal Physiol. 2005; 289(2):F459-68. DOI: 10.1152/ajprenal.00040.2005. View

de Reijke T, de Boer E, Kurth K, Schamhart D . Urinary cytokines during intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J Urol. 1996; 155(2):477-82. View

Shi M, Meng X, Fontugne J, Chen C, Radvanyi F, Bernard-Pierrot I . Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer. Genome Med. 2020; 12(1):85. PMC: 7646471. DOI: 10.1186/s13073-020-00781-y. View

Taniguchi K, Koga S, Nishikido M, Yamashita S, Sakuragi T, Kanetake H . Systemic immune response after intravesical instillation of bacille Calmette-Guérin (BCG) for superficial bladder cancer. Clin Exp Immunol. 1999; 115(1):131-5. PMC: 1905203. DOI: 10.1046/j.1365-2249.1999.00756.x. View

Seo W, Lee C, Jung S, Lee D, Park H, Jeong D . Expression of VISTA on tumor-infiltrating immune cells correlated with short intravesical recurrence in non-muscle-invasive bladder cancer. Cancer Immunol Immunother. 2021; 70(11):3113-3122. PMC: 10992450. DOI: 10.1007/s00262-021-02906-7. View

Kuo P, Zeng Z, Salim N, Mattarollo S, Wells J, Leggatt G . The Role of CXCR3 and Its Chemokine Ligands in Skin Disease and Cancer. Front Med (Lausanne). 2018; 5:271. PMC: 6167486. DOI: 10.3389/fmed.2018.00271. View

10.

Pimentel H, Bray N, Puente S, Melsted P, Pachter L . Differential analysis of RNA-seq incorporating quantification uncertainty. Nat Methods. 2017; 14(7):687-690. DOI: 10.1038/nmeth.4324. View

11.

Sato Y, Bolzenius J, Eteleeb A, Su X, Maher C, Sehn J . CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade. JCI Insight. 2018; 3(23). PMC: 6328023. DOI: 10.1172/jci.insight.121062. View

12.

Baker S, Shabir S, Southgate J . Biomimetic urothelial tissue models for the in vitro evaluation of barrier physiology and bladder drug efficacy. Mol Pharm. 2014; 11(7):1964-70. DOI: 10.1021/mp500065m. View

13.

Robertson A, Groeneveld C, Jordan B, Lin X, McLaughlin K, Das A . Identification of Differential Tumor Subtypes of T1 Bladder Cancer. Eur Urol. 2020; 78(4):533-537. DOI: 10.1016/j.eururo.2020.06.048. View

14.

Bray N, Pimentel H, Melsted P, Pachter L . Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016; 34(5):525-7. DOI: 10.1038/nbt.3519. View

15.

Southgate J, Hutton K, THOMAS D, Trejdosiewicz L . Normal human urothelial cells in vitro: proliferation and induction of stratification. Lab Invest. 1994; 71(4):583-94. View

16.

Kamoun A, De Reynies A, Allory Y, Sjodahl G, Robertson A, Seiler R . A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2019; 77(4):420-433. PMC: 7690647. DOI: 10.1016/j.eururo.2019.09.006. View

17.

Smith N, Varley C, Eardley I, Feather S, Trejdosiewicz L, Southgate J . Toll-like receptor responses of normal human urothelial cells to bacterial flagellin and lipopolysaccharide. J Urol. 2011; 186(3):1084-92. DOI: 10.1016/j.juro.2011.04.112. View

18.

Baker S, Mason A, Slip R, Skinner K, MacDonald A, Masood O . Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer. Oncogene. 2022; 41(15):2139-2151. PMC: 8862006. DOI: 10.1038/s41388-022-02235-8. View

19.

Robertson A, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack A . Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017; 171(3):540-556.e25. PMC: 5687509. DOI: 10.1016/j.cell.2017.09.007. View

20.

Stenehjem D, Tran D, Nkrumah M, Gupta S . PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer. Onco Targets Ther. 2018; 11:5973-5989. PMC: 6157986. DOI: 10.2147/OTT.S135157. View