The CHI3L1-neutrophil axis drives immune suppression and breast cancer metastatic dissemination
Tarek Taifour, Adéline Massé, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Emilie Solymoss, Yunyun Shen, Hailey Proud, Sherif Samer Attalla, Vasilios Papavasiliou, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Chun Geun Lee, Suchitra Kamle, Josie Ursini-Siegel, Jack A. Elias, Peter M. Siegel, Rinath Jeselsohn, William J. Muller
Tarek Taifour, Adéline Massé, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Emilie Solymoss, Yunyun Shen, Hailey Proud, Sherif Samer Attalla, Vasilios Papavasiliou, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Chun Geun Lee, Suchitra Kamle, Josie Ursini-Siegel, Jack A. Elias, Peter M. Siegel, Rinath Jeselsohn, William J. Muller
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Research Article Immunology Oncology

The CHI3L1-neutrophil axis drives immune suppression and breast cancer metastatic dissemination

Abstract

Immunosuppression and metastasis are critical hallmarks of breast cancer, often linked to poor patient outcomes. The secreted cytokine chitinase-3–like 1 (CHI3L1) is frequently overexpressed in breast cancer samples and promotes an immunosuppressed tumor microenvironment. Notably, CHI3L1 expression is elevated in metastatic patient samples when compared with the matched primary breast tumor. To investigate its role in breast cancer metastasis, we generated an inducible genetically engineered mouse model that overexpresses CHI3L1 in the mammary epithelium. Ectopic expression of CHI3L1 in the polyomavirus middle T (PyMT) mouse model of breast cancer suppressed antitumor immune responses, accelerated mammary tumor onset, and enhanced lung metastasis. Mechanistically, elevated CHI3L1 expression in the mammary epithelium enhanced neutrophil recruitment, which subsequently degraded the extracellular matrix and increased the number of circulating tumor cells. These findings reveal a key mechanism driving metastatic dissemination and argue that therapeutically targeting Chi3l1 could enhance antitumor immunity and suppress metastasis.

Authors

Tarek Taifour, Adéline Massé, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Emilie Solymoss, Yunyun Shen, Hailey Proud, Sherif Samer Attalla, Vasilios Papavasiliou, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Chun Geun Lee, Suchitra Kamle, Josie Ursini-Siegel, Jack A. Elias, Peter M. Siegel, Rinath Jeselsohn, William J. Muller

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Figure 4

Chi3l1 OE enhances metastatic dissemination through neutrophil-mediated ECM remodeling.

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Chi3l1 OE enhances metastatic dissemination through neutrophil-mediated ...
(A) H&E staining of WT, Chi3l1 OE, Stat3–/–, and Stat3–/– Chi3l1 OE MIC lungs at mammary tumor endpoint. (B) Percentage of WT (n = 12), Chi3l1 OE (n = 8), Stat3–/– (n = 13), and Stat3–/– Chi3l1 OE (n = 11) MIC mice with pulmonary metastases. (C) Quantification of metastatic area (percent total lung area) in WT (n = 12), Chi3l1 OE (n = 8), Stat3–/– (n = 13), and Stat3–/– Chi3l1 OE (n = 11) MIC lungs. (D) Quantification of PyMT+ cells (percent live cells in blood) of WT (n = 4) and Chi3l1 OE (n = 3) MIC mice. (E) FACS for circulating PyMT+ cells in WT and Chi3l1 OE MIC blood at 2 weeks after induction. (F) Staining of WT and Chi3l1 OE MIC mammary glands at 2 weeks after induction for laminin, collagen IV, pan-CK, and DAPI. (G and H) Quantification of area occupied by laminin or collagen IV (percent total mammary gland area) in WT (n = 7) and Chi3l1 OE (n = 8) MIC mammary glands. (I) FACS for circulating PyMT+ cells in blood of Chi3l1 OE MIC mice after anti-Ly6G or IgG2a treatment for 2 weeks. (J) Quantification of PyMT+ cells (percent live cells in the blood) of Chi3l1 OE MIC mice treated with IgG2a (n = 6) or anti-Ly6G (n = 5). (K) Staining of mammary tissue from MIC Chi3l1 OE mice treated with anti-Ly6G or IgG2a for laminin, collagen IV, pan-CK, and DAPI. (L and M) Quantification of area occupied by laminin and collagen IV (percent mammary gland area) in IgG2a-treated (n = 6) and anti-Ly6G–treated (n = 8) MIC Chi3l1 OE mammary glands. (N) Schematic of Transwell invasion assay through synthetic ECM. Created in BioRender (Muller W, 2026, https://BioRender.com/4lhz2a3). (O) ECM-invading PyMT+ cells with PBS, rmChi3l1, or murine neutrophils, stained with crystal violet. Neutrophils + PBS (no PyMT cells) is shown as negative control. (P) Quantification of invading PyMT+ cells. n = 3 technical replicates for each condition. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA with Tukey’s post hoc test (C and P) or by unpaired Student’s t test (for D, G, H, J, L, and M). Scale bars: 1 cm in A, left panels; 1 mm in A, right panels; 100 μm in F, K, and O.