Back to Search
Start Over
Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma
- Source :
- OncoImmunology, Vol 9, Iss 1 (2020), Oncoimmunology
- Publication Year :
- 2020
- Publisher :
- Taylor & Francis Group, 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Metastatic Urothelial Carcinoma
T cell
medicine.medical_treatment
Immunology
macrophage
CD8-Positive T-Lymphocytes
Lymphocyte Activation
T-Lymphocytes, Regulatory
03 medical and health sciences
Mice
0302 clinical medicine
Immune system
Immunology and Allergy
Medicine
Macrophage
Animals
Humans
Survival rate
RC254-282
Original Research
Response rate (survey)
Carcinoma, Transitional Cell
Bladder cancer
business.industry
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunotherapy
RC581-607
medicine.disease
t cell
030104 developmental biology
medicine.anatomical_structure
checkpoint inhibitor
Oncology
Urinary Bladder Neoplasms
030220 oncology & carcinogenesis
Cancer research
bladder cancer
immunotherapy
Immunologic diseases. Allergy
business
Subjects
Details
- Language :
- English
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- OncoImmunology
- Accession number :
- edsair.doi.dedup.....1a98d2e3ebe35a97fc3d5694f7248d5c