Anti‐interleukin‐10R1 monoclonal antibody in combination with bacillus Calmette–Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti‐tumour immunity

M. R Newton; E. J Askeland; E. D Andresen; V. A Chehval; X Wang; R. W Askeland; M. A O'Donnell; Y Luo

doi:10.1111/cei.12315

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Anti‐interleukin‐10R1 monoclonal antibody in combination with bacillus Calmette–Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti‐tumour immunity

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Anti‐interleukin‐10R1 monoclonal antibody in combination with bacillus Calmette–Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti‐tumour immunity

M. R Newton, E. J Askeland, E. D Andresen, V. A Chehval, X Wang, R. W Askeland, M. A O'Donnell and Y Luo

Clinical and experimental immunology, Vol.177(1), pp.261-268

07/2014

DOI: 10.1111/cei.12315

PMCID: PMC4089175

PMID: 24593764

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Abstract

Summary Effective treatment of bladder cancer with bacillus Calmette–Guérin (BCG) depends on the induction of a T helper type (Th) 1 immune response. Interleukin (IL)‐10 down‐regulates the Th1 response and is associated with BCG failure. In this study, we investigated whether blocking IL‐10 signalling could enhance the BCG‐induced Th1 response and anti‐tumour immunity in a murine orthotopic tumour model. Treatment with BCG and anti‐IL‐10 receptor 1 monoclonal antibody (anti‐IL‐10R1 mAb) increased the interferon (IFN)‐γ to IL‐10 ratio in both splenocyte cultures and urine. Mice bearing luciferase‐expressing MB49 (MB49‐Luc) tumours were treated and followed for tumour growth by bioluminescent imaging, bladder weight and histology. Mice treated with phosphate‐buffered saline (PBS) (group 1), BCG plus control immunoglobulin (Ig)G1 (group 2) or BCG plus anti‐IL‐10R1 mAb (group 3) showed 0, 6 and 22% tumour regression, respectively. The mean bladder weight of group 3 mice was substantially lower than those of groups 1 and 2 mice. Remarkably, 36% of group 1 and 53% of group 2 mice but no group 3 mice developed lung metastasis (P = 0·02). To investigate the mechanisms underlying the effect of combination therapy, splenocytes were stimulated with S12 peptide (serine mutation at codon 12 of the K‐ras oncogene) known to be expressed in MB49‐Luc cells. Induction of ras mutation‐specific IFN‐γ and cytotoxicity was observed in mice treated with combination therapy. These observations indicate that BCG, in combination with anti‐IL‐10R1 mAb, induces enhanced anti‐tumour immunity that is protective against lung metastasis. Anti‐IL‐10R1 mAb demonstrates systemic effects and may prove useful in clinical practice for treating bladder cancer in high‐risk patients.

Bladder Cancer

Immunotherapy

IL‐10

BCG

Details

Title: Subtitle: Anti‐interleukin‐10R1 monoclonal antibody in combination with bacillus Calmette–Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti‐tumour immunity
Creators: M. R Newton - University of Iowa
E. J Askeland - University of Iowa
E. D Andresen - University of Iowa
V. A Chehval - University of Iowa
X Wang - University of Iowa
R. W Askeland - University of Iowa
M. A O'Donnell - University of Iowa
Y Luo - University of Iowa
Resource Type: Journal article
Publication Details: Clinical and experimental immunology, Vol.177(1), pp.261-268
DOI: 10.1111/cei.12315
PMID: 24593764
PMCID: PMC4089175
NLM abbreviation: Clin Exp Immunol
ISSN: 0009-9104
eISSN: 1365-2249
Number of pages: 8
Grant note: Pfizer Inc.
Language: English
Date published: 07/2014
Academic Unit: Urology
Record Identifier: 9984051581502771

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