PT - JOURNAL ARTICLE AU - Joseph R. Podojil AU - Alexander P. Glaser AU - Dylan Baker AU - Elise T. Courtois AU - Damiano Fantini AU - Yanni Yu AU - Valerie Eaton AU - Santhosh Sivajothi AU - Paul Robson AU - Stephen D. Miller AU - Joshua J. Meeks TI - Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma AID - 10.1101/730564 DP - 2019 Jan 01 TA - bioRxiv PG - 730564 4099 - http://biorxiv.org/content/early/2019/08/10/730564.short 4100 - http://biorxiv.org/content/early/2019/08/10/730564.full AB - Locally advanced urothelial carcinoma has a poor survival despite a response to immunotherapy in approximately 25% of patients. To develop new therapies targeting other immune checkpoints, we identified increased expression of the T cell inhibitor protein, B7-H4 (VTCN1, B7S1, B7X), during tumor development of murine bladder cancer. Evaluation of B7-H4 in human bladder cancer by single-cell RNA-Seq and immune mass cytometry showed that B7-H4 is expressed by luminal tumors that are not normally responsive to PD-1 inhibitors. Additionally, overexpression B7-H4 was associated with significantly worse patient survival. In support of clinical translation, 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 cell. While the study of B7-H4 in mouse cancer models has been difficult using tumor cell lines, our findings show that B7-H4 expression increased at 3 months after exposure to BBN on CD11b+ monocytes/macrophages and delivery of anti-B7-H4 antibody resulted in decreased tumor size and increased CD8 immune cell infiltration with increased CD8+/IFN-γ-producing T cells 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. This data suggests that novel anti-B7-H4 antibodies maybe a viable target for bladder cancers unresponsive to PD-1 checkpoint inhibitors.