| dc.description.abstract | Breast cancer remains the second leading cause of cancer-related deaths among females. The abundance of clinical trials reveals the extent to which investigators are attempting novel therapies for patients at risk. Immune checkpoint inhibitor (ICI) therapy, including anti-PD-1/anti-PD-L1 monoclonal antibodies, has seen broad success in several cancer types, including breast cancer. However, one of the challenges in the deployment of these therapies is determining which patients will benefit. In the present studies, we investigated whether the alternate immune checkpoint ligand B7-H4 could be contributing to immunotherapy resistance in certain breast cancer patients. B7-H4 (encoded by VTCN1) is an immune checkpoint ligand in the CD28/B7 family of molecules, which includes PD-1/PD-L1. First, we identified that in triple-negative breast cancers (TNBCs), B7-H4 was highly expressed in tumors lacking an abundant immune infiltrate and was correlated with worse patient survival. Second, we discovered B7-H4 is preferentially expressed on epithelial tumor cells in mouse and human breast cancer cell lines and in TNBC. Third, we validated that, unlike the immune checkpoint ligand PD-L1, B7-H4 is regulated by PI3K signaling in human and murine breast cancers. Finally, we observed B7-H4 caused immunotherapy resistance in a murine mammary cancer model due to inhibition of pro-inflammatory immune cell activation, but conversely in human cancers, B7-H4 expression was associated with improved response to immunotherapy plus chemotherapy. These data collectively show the importance of validating murine study results in human clinical trials and suggest B7-H4 may have different functions in patient tumors. Therefore, it may not be an appropriate target for antibody blocking therapies but perhaps more suited to antibody-drug-conjugate therapies. | |
