FIGURE 6 from Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

https://doi.org/10.1158/2767-9764.25683738

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posted on 2024-04-24, 14:20 authored by 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. Lehmann, Vandana G. Abramson, Gillian L. Hirst, Lamorna Brown Swigart, Laura J. van ˈt Veer, Laura J. Esserman, Emanuel F. Petricoin, Jennifer A. Pietenpol, Justin M. Balko

B7-H4 expression does not correlate with resistance to chemotherapy + immunotherapy in human breast tumors. Patients were from the I-SPY2 clinical trial (paclitaxel control and pembrolizumab arms) or the TBCRC 043 clinical trial (carboplatin control and atezolizumab arms). A, In breast tumors from the I-SPY2 clinical trial (control and pembrolizumab arms), B7-H4 expression is higher in TNBC tumors compared with HR+ tumors. Data were analyzed by unpaired t test. B, In the same patient cohort, B7-H4 expression is not higher in grade III tumors compared with grade I (orange dots) or II. Data analyzed by unpaired t test. C and D, B7-H4 expression is not correlated with pCR in tumors regardless of HR status, treated with either paclitaxel or paclitaxel + pembrolizumab (ICI). Data analyzed by unpaired t test. E, EFS in HR+ (n = 89) and TNBC (n = 62) tumors from the I-SPY2 cohort. Tumors with high B7-H4+ expression (top 33% of patients) have worse EFS when treated with paclitaxel alone and no survival benefit when treated with paclitaxel + ICI. Data were analyzed by log-rank Mantel–Cox test. F, In the metastatic setting, PFS stratified by B7-H4 expression (top and bottom 33% of cohort) from primary breast biopsy or metastatic lesion in patients from the TBCRC 043 trial does not correlate with B7-H4 expression in either control or carboplatin + atezolizumab (ICI) groups. Data were analyzed by log-rank Mantel–Cox test. G and H, We also assessed survival by treatment status. Metastatic tumors (H) from TBCRC 043 with high B7-H4 expression had significantly improved PFS to ICI, and nonmetastatic tumors (I-SPY2) had minimal improvement to ICI (G). Data were analyzed by log-rank Mantel–Cox test. n = 151 patients for A–E and G; n = 91 patients for F and H.

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HHS | NIH | National Cancer Institute (NCI)

U.S. Department of Defense (DOD)

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DOI - Is supplement to Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

ARTICLE 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. 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.