Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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

×

Figure 2

Patient-derived stromal cells promote MDSC recruitment into the TME.

Options: View larger image (or click on image) Download as PowerPoint
Patient-derived stromal cells promote MDSC recruitment into the TME.
MDS...
MDSCs were analyzed by multicolor IHC on Arg1/CD11b/GR1/GFP. (A) Representative images of multicolor IHC detecting GFP (green), Arg1 (yellow), CD11b (white), and GR1 (red). Arrowheads indicate positive stromal cells. Dotted lines represent the boundary of the tumor (Tu) and stroma (St) area. Nuclei are stained with DAPI. Scale bars: 50 μm. (B) The rate of Arg1+CD11b+GR1+GFP+ cells (% of stromal cells). (C) The rate of Arg1+CD11b+GR1+GFP+ cells (% of GFP+ cells). HSC-2, HSC-2–alone xenograft; +HDF, HSC-2 + HDF coxenograft; +PDS1, HSC-2 + PDS1 coxenograft; +PDS2, HSC-2 + PDS2 coxenograft (5 fields per mouse, n = 6). All data are shown as mean ± SD. Statistical analyses were performed using 1-way ANOVA followed by Tukey’s multiple-comparison post hoc test; ****P < 0.0001.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts