Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer

Seunghyun Lee, Biancamaria Ricci, Jennifer Tran, Emily Eul, Jiayu Ye, Qihao Ren, David Clever, Julia Wang, Pamela Wong, Michael S. Haas, Sheila A. Stewart, Cynthia X. Ma, Todd A. Fehniger and Roberta Faccio ()
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Seunghyun Lee: Washington University School of Medicine
Biancamaria Ricci: Washington University School of Medicine
Jennifer Tran: Washington University School of Medicine
Emily Eul: Washington University School of Medicine
Jiayu Ye: Washington University School of Medicine
Qihao Ren: Washington University School of Medicine
David Clever: Washington University School of Medicine
Julia Wang: Washington University School of Medicine
Pamela Wong: Washington University School of Medicine
Michael S. Haas: Leap Therapeutics
Sheila A. Stewart: Washington University School of Medicine
Cynthia X. Ma: Washington University School of Medicine
Todd A. Fehniger: Washington University School of Medicine
Roberta Faccio: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.

Date: 2025
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DOI: 10.1038/s41467-025-56420-w

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