Wescott, Elizabeth C.Sun, XiaopengGonzalez-Ericsson, PaulaHanna, AnnTaylor, Brandie C.Sanchez, VioletaBronzini, JulianaOpalenik, Susan R.Sanders, Melinda E.Wulfkuhle, JuliaGallagher, Rosa I.Gomez, HenryIsaacs, ClaudineBharti, VijayaWilson, John T.Ballinger, Tarah J.Santa-Maria, Cesar A.Shah, Payal D.Dees, Elizabeth C.Lehmann, Brian D.Abramson, Vandana G.Hirst, Gillian L.Brown Swigart, Lamornavan ˈt Veer, Laura J.Esserman, Laura J.Petricoin, Emanuel F.Pietenpol, Jennifer A.Balko, Justin M.2024-07-122024-07-122024Wescott EC, Sun X, Gonzalez-Ericsson P, et al. Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer. Cancer Res Commun. 2024;4(4):1120-1134. doi:10.1158/2767-9764.CRC-23-0468https://hdl.handle.net/1805/42164Combinations 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.en-USAttribution 4.0 InternationalB7-H1 antigenBreast neoplasmsEpithelial cellsImmune checkpoint inhibitorsTriple negative breast neoplasmsArticle