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 6

C1q disrupts CD8+ T cell metabolism, enabling immune evasion in resistant tumors.

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C1q disrupts CD8+ T cell metabolism, enabling immune evasion in resistan...
(A) Growth of E0771-Res1 tumor in CCR2-KO mice receiving WT or TREM2-KO monocytes, under combined therapy (n = 5). Arrowheads indicate monocyte transfers. (B) Representative flow plots showing CFSE dilution and CD25 expression in CD8+ T cell treated with activation beads and indicated concentrations of murine C1q. (C–E) Quantification of total CD8+ T cells (C), CD25+/total CD8+ T cell ratios (D), and IFN-γ production by CD8+ T cells (E). (F) Quantification of surviving E0771-OVA cells after coculture with pretreated OT-1 CD8+ T cells. (G) ELISA quantification of C1q in tumor lysates from E0771, E0771-Res1, and E0771-Res2 tumors (n = 4). (H) Immunofluorescence of MitoTracker Deep Red, C1q, C1QBP, and DAPI in CD8+ T cells. Scale bar: 1 μm. (I) Immunoblot of OPA1, DRP1, and phosphor-DRP1 (Ser616) in CD8+ T cells. (Bottom) Quantification of DRP1 levels normalized to β-ACTIN (3 independent experiments). (J) TEM images of activated CD8+ T cells treated with vehicle or C1q for 48 hours. Scale bar: 2 μm; 0.5 μm (zoomed-in). (K) Representative flow plots of MitoTracker Deep Red/Green (MDR/MG) populations. (L and M) CD25 expression (L) and IFN-γ production (M) in MDR/MGlo versus MDR/MGhi CD8+ T cells. (N) Representative plots and quantification of MDR/MGhi CD8+ T cells from E0771-Res1 tumors in WT (n = 5) or C1qa-KO mice (n = 4). (O) Growth of E0771-Res2 tumors in WT or C1qa-KO mice under vehicle or combined therapy. The values 0.2266 and 1.5 × 104 indicate represent P values for the comparison of tumor volumes between the combined paclitaxel and anti–PD-1 treatment group and the vehicle control at day 18, in wild-type and C1qa knockout mice, respectively. (P) Tumor growth of E0771-Res1 tumors in CCR2-KO mice receiving WT or C1qa-KO monocytes under combined therapy (n = 5). (Q) Flow cytometry of CD8+ T cells from tumors in P. Significance was calculated using 1-way ANOVA followed by Tukey’s test (C–G, and I); unpaired 2-tailed Student’s t test (A and L–Q). *P < 0.05, **P < 0.005, ***P < 0.001, ****P < 0.0001.