Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
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Research Article Immunology Oncology

Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer

Abstract

Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes — proinflammatory and proresolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas proresolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After chemoimmunotherapy, mesenchymal-like tumors expanded proresolution macrophages through phagocytosis/efferocytosis, ω-3 fatty acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via ω-6 fatty acid pathways. Knocking down ELOVL5 — an elongase involved in ω-3 and ω-6 metabolism — mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.

Authors

Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang

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Figure 4

Monocyte-derived tumor-associated macrophages are key mediators of therapy resistance.

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Monocyte-derived tumor-associated macrophages are key mediators of thera...
(A) Schematic of the experimental design: Combined treatments started on day 3 after tumor implantation. Anti–M-CSF plus clodrosome or control IgG1 plus liposome were administered as indicated. (B) Flow cytometry of PB monocytes in E0771-Res1 tumor-bearing mice under control or combined therapy, with or without macrophage depletion (n = 5). (C) Representative immunohistochemistry of F4/80 in E0771-Res1 tumors treated with control IgG plus liposome or anti–M-CSF plus clodrosome. Scale bar: 100 μm. (D) Tumor growth of E0771-Res1 tumors under vehicle or combined therapy, with or without macrophage depletion (n = 5). The values 5.04 × 103 and 4.31 × 10–4 represent P values for the comparison of tumor volumes between combined paclitaxel and anti–PD-1 treatment and vehicle control at day 24 in control and macrophage-depleted mice, respectively. (E) Flow cytometry of immune infiltrates in E0771-Res1 tumors at endpoint. (Left) Log2 fold change of major immune cells relative to the vehicle-treated tumor group. (Right) Average immune cell number per 1,000 CD45– cells. (F) Quantification of major immune cells per 1,000 CD45– cells in E0771-Res1 tumors under indicated treatments. (G) PB monocytes in E0771-Res1 tumor-bearing WT or CCR2-KO mice treated with control or combined treatment. Samples collected on day 1 and 17 after implantation. Significance was calculated using paired 2-tailed Student’s t test. (H and I) Growth of E0771-Res1 (H) and T12 tumors (I) in WT or CCR2-KO mice treated with vehicle or PTX combined with anti–PD-1 (n = 5 mice per group). (J) Flow cytometry analysis of the immune infiltrates in E0771-Res1 tumors. (Left) Log2 fold change of major immune cells relative to the vehicle-treated tumor group. (Right) Average immune cell number per 1,000 CD45– cells. (K) Quantification of major immune cells per 1,000 CD45– cells in E0771-Res1 tumors in WT versus CCR2-KO mice. (B, D, F, H, I, and K) Statistical significance was determined using 1-way ANOVA followed by Tukey’s test. *P < 0.05, **P < 0.005, ***P < 0.001, ****P < 0.0001.