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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

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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 1

The myeloid-biased differentiation of splenic early HSPCs from Hepa mice.

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The myeloid-biased differentiation of splenic early HSPCs from Hepa mice...
(A) Analysis of peripheral blood myeloid cell (CD11b+Gr-1+) and lymphocyte (CD3+ T and B220+ B cells) reconstitution chimerisms in recipient mice (BM, n = 7 mice per group; spleen, n = 9 mice per group). *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA with Bonferroni’s correction. (B) Quantification of CFU-C activity in BM and spleens from control (n = 7) and Hepa (n = 8) mice. ***P < 0.001, by Student’s t test. BFU-E, burst-forming unit–erythroid. (C) CFU-S12 activity of 500 BM-derived (n = 15 recipients) or splenic (n = 21 recipients) LSK cells from Hepa mice. ***P < 0.001, by Student’s t test. (D) Scheme of the 2-step single-cell colony-forming assay, representative colonies, and the percentage of different types of lineage readouts of the secondary CFU-C. Scale bars: 500 μm. Numbers above the columns represent the sample size of the initiating single cells in each group. Results are shown as the mean ± SEM of mice in each group (A–C). Data are from 2 experiments (A and B) or 3 experiments, with cells pooled from 6 to 10 mice (C and D).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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