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

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 2

Accumulation of GM-CSF–expressing LSK cells in the spleens of tumor-bearing mice.

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Accumulation of GM-CSF–expressing LSK cells in the spleens of tumor-bear...
(A) Endogenous GM-CSF expression in freshly isolated LSK cells and GMPs (FcγRhiCD34+ LK) (n = 6 per group). ***P < 0.001, by 2-way ANOVA followed by Dunnett’s test. (B) Immunoblot for NF-κB p65 and MAPK p38 activation in LSK cells isolated from BM and spleens of Hepa mice. p, phosphorylated; t, total. (C) Clonogenic ability of 500 BM or splenic LSK cells isolated from Hepa mice (n = 6 per group) in the methylcellulose-based assay. Anti–GM-CSF (αGM-CSF): 3 μg/ml. ***P < 0.001, by 2-way ANOVA followed by Dunnett’s test. (D) LSK cells were CFSE stained and cultured for 5 days in serum-free medium supplemented with SCF and the indicated concentration of anti–GM-CSF Abs in the cultures. The proliferation and differentiation HSPCs into myeloid cells are shown by CFSE dilution. (E) GM-CSF expression in LSK cells was examined after 24 hours of the cultures described in D. Numbers in the flow cytometric plots indicate the proportions of gated cells (A, D, and E). Results are shown as the mean ± SEM for mice in each group (A and C). Data are from 2 experiments (A), 3 experiments with cells pooled from 6 to 10 mice (C), or representative of at least 3 experiments (B, D, and E).