Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

Elizabeth C. Wescott, Xiaopeng Sun, Paula Gonzalez-Ericsson, Ann Hanna, Brandie C. Taylor, Violeta Sanchez, Juliana Bronzini, Susan R. Opalenik, Melinda E. Sanders, Julia Wulfkuhle, Rosa I. Gallagher, Henry Gomez, Claudine Isaacs, Vijaya Bharti, John T. Wilson, Tarah J. Ballinger, Cesar A. Santa-Maria, Payal D. Shah, Elizabeth C. Dees, Brian D. LehmannVandana G. Abramson, Gillian L. Hirst, Lamorna Brown Swigart, Laura J. van't Veer, Laura J. Esserman, Emanuel F. Petricoin, Jennifer A. Pietenpol, Justin M. Balko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1120-1134
Number of pages15
JournalCancer research communications
Volume4
Issue number4
DOIs
StatePublished - Apr 2024
Externally publishedYes

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