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Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment
May Wathone Oo, … , Akira Sasaki, Hitoshi Nagatsuka
May Wathone Oo, … , Akira Sasaki, Hitoshi Nagatsuka
Published December 7, 2021
Citation Information: JCI Insight. ;7(1):e148960. https://doi.org/10.1172/jci.insight.148960.
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Research Article Oncology

Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment

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Abstract

Accumulating evidence has shown that cancer stroma and BM-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here, we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (a) BM transplantation of GFP-expressing cells and (b) coxenografting of patient-derived stroma (PDS; 2 cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDC migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS coxenografts recruited Arginase-1+CD11b+GR1+GFP+ cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF coxenograft did not. Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2+ stromal cells and CCR2+Arginase-1+CD11b+GR1+ MDSCs (as receiver cells) than the HDF coxenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, i.p. injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2+Arginase-1+CD11b+GR1+ MDSC infiltration to the TME. In conclusion, oral cancer stroma–secreted CCL2 is a key signal for recruiting CCR2+ MDSCs from BM to the TME.

Authors

May Wathone Oo, Hotaka Kawai, Kiyofumi Takabatake, Shuta Tomida, Takanori Eguchi, Kisho Ono, Qiusheng Shan, Toshiaki Ohara, Saori Yoshida, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Kuniaki Okamoto, Akira Sasaki, Hitoshi Nagatsuka

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Figure 3

Comprehensive analysis of cellular chemotaxis–related genes revealed that CCL2 mRNA was highly expressed in the patient-derived stroma.

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Comprehensive analysis of cellular chemotaxis–related genes revealed tha...
(A) Flow chart of cellular chemotaxis–related genes screening. We analyzed the differentially expressed genes (DEGs) of oral squamous cell carcinoma (OSCC) PDS1 and PDS2 compared with HDF with the cut-off of more than 3 times of SD. We selected the common DEGs by Venny 2.1 and observed the cellular chemotaxis–related genes by DAVID bioinformatics Resources 6.8. (B) Venn diagram for commonly upregulated and downregulated gene expression among OSCC-PDS1 and OSCC-PDS2, and list of 15 cellular chemotaxis–related genes shared by PDS1 and PDS2. (C) Relative mRNA expression levels of 15 cellular chemotaxis genes in HDF, PDS1, and PDS2. (D) Heatmap presentation of the expression level of cellular chemotaxis genes in HDF, PDS1, and PDS2.

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