Loss of Cxcr2 in myeloid cells promotes tumour progression and T cell infiltration in invasive bladder cancer

Ismail, N. F. B., Foth, M., Yousef, A. R. E., Cui, N., Leach, J. D.G., Jamieson, T., Karim, S. A., Salmond, J. M., Morton, J. P. and Iwata, T. (2022) Loss of Cxcr2 in myeloid cells promotes tumour progression and T cell infiltration in invasive bladder cancer. Bladder Cancer, 8(3), pp. 277-290. (doi: 10.3233/BLC-211645)

Abstract

BACKGROUND:CXCR2 is a chemokine receptor expressed in myeloid cells, including neutrophils and macrophages. Pharmacological inhibition of CXCR2 has been shown to sensitize tumours to immune checkpoint inhibitor immunotherapies in some cancer types. OBJECTIVE:To investigate the effects of CXCR2 loss in regulation of tumour-infiltrating myeloid cells and their relationship to lymphocytes during bladder tumorigenesis. METHODS:Urothelial pathogenesis and immune contexture was investigated in an OH-BBN model of invasive bladder cancer with Cxcr2 deleted in myeloid cells (LysMCre Cxcr2floxflox). CXCR2 gene alterations and expression in human muscle invasive bladder cancer were analysed in The Cancer Genome Atlas. RESULTS:Urothelial tumour pathogenesis was significantly increased upon Cxcr2 deletion compared to wildtype mice. This was associated with a suppression of myeloid cell infiltration in Cxcr2-deleted bladders shortly after the carcinogen induction. Interestingly, following a transient increase of macrophages at the outset of tumour formation, an increase in T cell infiltration was observed in Cxcr2-deleted tumours. The increased tumour burden in the Cxcr2-deleted bladder was largely independent of T cells and the status of immune suppression. The Cxcr2-deleted mouse model reflected the low CXCR2 mRNA range in human bladder cancer, which showed poor overall survival. CONCLUSIONS:In contrast to previous reports of increased CXCR2 signalling associated with disease progression and poor prognosis, CXCR2 was protective against bladder cancer during tumour initiation. This is likely due to a suppression of acute inflammation. The strategy for sensitizing checkpoint immunotherapy by CXCR2 inhibition in bladder cancer may benefit from an examination of immune suppressive status.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leach, Dr Joshua and Yousef, Amal Rahil Elgaddafi and Morton, Professor Jen and Iwata, Dr Tomoko and Karim, Ms Saadia and ISMAIL, NUR FAEZAH BINTI and Salmond, Dr Jonathan and Cui, Ningxuan and Jamieson, Mr Thomas
• Authors: Ismail, N. F. B., Foth, M., Yousef, A. R. E., Cui, N., Leach, J. D.G., Jamieson, T., Karim, S. A., Salmond, J. M., Morton, J. P., and Iwata, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Bladder Cancer
• Publisher: IOS Press
• ISSN: 2352-3727
• ISSN (Online): 2352-3735
• Published Online: 01 June 2022
• Copyright Holders: Copyright © 2022 IOS Press
• First Published: First published in Bladder Cancer 8(3): 277-290
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172879		Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancer	Owen Sansom	Medical Research Council (MRC)	MR/N021800/1	CS - Beatson Institute for Cancer Research