ArticleCancer research communications2024
Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.
Article in Cancer research communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Ubiquitin-driven regulation of immune checkpoints in lung cancer: Mechanisms and therapeutic implications (Review).Experimental and therapeutic medicine · 2026Review
- A study on the mechanism of action of B7H4 in HER2-positive gastric cancer and its sensitivity to trastuzumab therapy.Translational cancer research · 2026Article
- FcγR-driven chimeric receptor T cells in cancer therapy: a novel frontier in antibody-guided immunotherapy.Cancer cell international · 2026Review
- Article
- Breaking Barriers: Immune Checkpoint Inhibitors in Breast Cancer.Pharmaceutics · 2025Review
- The Impact of JAK1 Pathogenic Variants and MHC-I Expression on Response to Immune Checkpoint Inhibition in Endometrial Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Elevated tumor NOS2/COX2 promotes immunosuppressive phenotypes associated with poor survival in ER- breast cancer.JCI insight · 2025Article
- A Novel B7-H4xCD3 Bispecific T-cell Engager (PF-07260437) Synergizes with Breast Cancer Standard of Care and Immune Checkpoint Therapies.Molecular cancer therapeutics · 2025Article
- Spatial Transcriptome Analysis of B7-H4 in Head and Neck Squamous Cell Carcinoma: A Novel Therapeutic Target for Anti-Immune Checkpoint Inhibitors.Head and neck pathology · 2025Article
- Article
- Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling.International journal of molecular sciences · 2024Article
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Authors and funding
28 authors.
Funding
Abstract
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.
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