Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma
Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1–17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatur...
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doaj-65b13dd77b67406ab5251edfaad726452021-09-24T14:41:24ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2020.17448971744897Antibody targeting of B7-H4 enhances the immune response in urothelial carcinomaJoseph R. Podojil0Alexander P. Glaser1Dylan Baker2Elise T. Courtois3Damiano Fantini4Yanni Yu5Valerie Eaton6Santhosh Sivajothi7Mingyi Chiang8Arighno Das9Kimberly A. McLaughlin10Paul Robson11Stephen D. Miller12Joshua J. Meeks13Feinberg School of MedicineFeinberg School of MedicineThe Jackson Laboratory for Genomic MedicineThe Jackson Laboratory for Genomic MedicineFeinberg School of MedicineFeinberg School of MedicineFeinberg School of MedicineThe Jackson Laboratory for Genomic MedicineFeinberg School of MedicineFeinberg School of MedicineFeinberg School of MedicineThe Jackson Laboratory for Genomic MedicineFeinberg School of MedicineFeinberg School of MedicinePatients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1–17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8+ T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors.http://dx.doi.org/10.1080/2162402X.2020.1744897immunotherapybladder cancermacrophaget cellcheckpoint inhibitor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joseph R. Podojil Alexander P. Glaser Dylan Baker Elise T. Courtois Damiano Fantini Yanni Yu Valerie Eaton Santhosh Sivajothi Mingyi Chiang Arighno Das Kimberly A. McLaughlin Paul Robson Stephen D. Miller Joshua J. Meeks |
spellingShingle |
Joseph R. Podojil Alexander P. Glaser Dylan Baker Elise T. Courtois Damiano Fantini Yanni Yu Valerie Eaton Santhosh Sivajothi Mingyi Chiang Arighno Das Kimberly A. McLaughlin Paul Robson Stephen D. Miller Joshua J. Meeks Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma OncoImmunology immunotherapy bladder cancer macrophage t cell checkpoint inhibitor |
author_facet |
Joseph R. Podojil Alexander P. Glaser Dylan Baker Elise T. Courtois Damiano Fantini Yanni Yu Valerie Eaton Santhosh Sivajothi Mingyi Chiang Arighno Das Kimberly A. McLaughlin Paul Robson Stephen D. Miller Joshua J. Meeks |
author_sort |
Joseph R. Podojil |
title |
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma |
title_short |
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma |
title_full |
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma |
title_fullStr |
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma |
title_full_unstemmed |
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma |
title_sort |
antibody targeting of b7-h4 enhances the immune response in urothelial carcinoma |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2020-01-01 |
description |
Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1–17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8+ T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors. |
topic |
immunotherapy bladder cancer macrophage t cell checkpoint inhibitor |
url |
http://dx.doi.org/10.1080/2162402X.2020.1744897 |
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