1. Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.
- Author
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Wescott, Elizabeth, Sun, Xiaopeng, Gonzalez-Ericsson, Paula, Hanna, Ann, Taylor, Brandie, Sanchez, Violeta, Bronzini, Juliana, Opalenik, Susan, Sanders, Melinda, Wulfkuhle, Julia, Gallagher, Rosa, Gomez, Henry, Isaacs, Claudine, Bharti, Vijaya, Wilson, John, Ballinger, Tarah, Santa-Maria, Cesar, Shah, Payal, Dees, Elizabeth, Lehmann, Brian, Abramson, Vandana, Brown Swigart, Lamorna, van ˈt Veer, Laura, Petricoin, Emanuel, Pietenpol, Jennifer, Balko, Justin, Esserman, Laura, and Hirst, Gillian
- Subjects
V-Set Domain-Containing T-Cell Activation Inhibitor 1 ,Animals ,Humans ,Mice ,Female ,Cell Line ,Tumor ,Immunotherapy ,Triple Negative Breast Neoplasms ,Immune Checkpoint Inhibitors ,Breast Neoplasms ,B7-H1 Antigen ,Epithelial Cells ,Gene Expression Regulation ,Neoplastic - Abstract
UNLABELLED: Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.
- Published
- 2024