Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis
Chong Wu, … , Min-Shan Chen, Limin Zheng
Chong Wu, … , Min-Shan Chen, Limin Zheng
Published May 17, 2018
Citation Information: J Clin Invest. 2018;128(8):3425-3438. https://doi.org/10.1172/JCI97973.
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Research Article Immunology Oncology Article has an altmetric score of 6

Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis

Abstract

Cancer progression is associated with alterations of intra- and extramedullary hematopoiesis to support a systemic tumor-promoting myeloid response. However, the functional specialty, mechanism, and clinical relevance of extramedullary hematopoiesis (EMH) remain unclear. Here, we showed that the heightened splenic myelopoiesis in tumor-bearing hosts was not only characterized by the accumulation of myeloid precursors, but also associated with profound functional alterations of splenic early hematopoietic stem/progenitor cells (HSPCs). With the distinct capability to produce and respond to granulocyte-macrophage CSF (GM-CSF), these splenic HSPCs were “primed” and committed to generating immunosuppressive myeloid cells. Mechanistically, the CCL2/CCR2 axis–dependent recruitment and the subsequent local education by the splenic stroma were critical for eliciting this splenic HSPC response. Selective abrogation of this splenic EMH was sufficient to synergistically enhance the therapeutic efficacy of immune checkpoint blockade. Clinically, patients with different types of solid tumors exhibited increased splenic HSPC levels associated with poor survival. These findings reveal a unique and important role of splenic hematopoiesis in tumor-associated myelopoiesis.

Authors

Chong Wu, Huiheng Ning, Mingyu Liu, Jie Lin, Shufeng Luo, Wenjie Zhu, Jing Xu, Wen-Chao Wu, Jing Liang, Chun-Kui Shao, Jiaqi Ren, Bin Wei, Jun Cui, Min-Shan Chen, Limin Zheng

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Figure 7

Abrogation of splenic EMH synergistically enhances anti–PD-L1 efficacy.

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Abrogation of splenic EMH synergistically enhances anti–PD-L1 efficacy. ...
(A) Survival of Hepa mice subjected to sham surgery or splenectomy with or without anti–PD-L1 treatment. *P < 0.001 and ***P < 0.001, by log-rank test compared with the sham group; ###P < 0.001, by log-rank test compared with the splenectomy group; †††P < 0.001, by log-rank test compared with the sham plus anti–PD-L1 group. (B) Fold changes in the numbers of splenic LSK and GMP cells in Hepa mice. ***P < 0.001, by 2-way ANOVA followed by Dunnett’s test. (C) Proportions of GM-CSF+ splenic LSK cells in Hepa mice. ***P < 0.001, by 2-way ANOVA followed by Dunnett’s test. (D–F) Immunosuppressive activity of tumor-infiltrating CD11b+Ly6G+Ly6Clo PMN-like cells (D and E) and the frequencies of tumor-infiltrating IFN-γ+CD3+CD8+ CTLs (F). Hepa mice were treated with low-dose sorafenib (Sora) 7 days prior to examination or were left untreated as controls. ***P < 0.001, by 2-way ANOVA with Bonferroni’s correction. (G) Survival of Hepa mice that received no treatment or treatment with low-dose sorafenib or anti–PD-L1 or both. For some groups, mice received adoptive transfers of 1 × 106 splenic HSPCs or 5 × 106 MDSCs 3 and 10 days after the latter dose of sorafenib. ***P < 0.001, by log-rank test compared with the isotype plus sorafenib group; ###P < 0.001, by log-rank test compared with the anti–PD-L1 group; †††P < 0.001, by log-rank test compared with the anti–PD-L1 plus sorafenib group. (H) Survival of CCR2+/+ or CCR2–/– Hepa mice treated with anti–PD-L1 or isotype Abs. ***P < 0.001, by log-rank test compared with the CCR2–/– plus isotype group; #P < 0.05, by log-rank test compared with the CCR2+/+ plus anti–PD-L1 group. Data are representative of 2 experiments (B–F; n = 3 per group in each experiment) and indicate the mean ± SEM, or were pooled from 2 experiments (n = 7–11 per group as indicated in A, G, and H).