Submitted January 31, 2008
Accepted March 8, 2008
Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice
Yasushi Sawanobori, Satoshi Ueha, Makoto Kurachi, Takeshi Shimaoka, James E. Talmadge, Jun Abe, Yusuke Shono, Masahiro Kitabatake, Kazuhiro Kakimi, Naofumi Mukaida, and Kouji Matsushima*
Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
Departent of Immunotherapeutics (Medinet), Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
Divisions of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
* Corresponding author; email: koujim{at}m.u-tokyo.ac.jp.
Tumor growth is associated with aberrant myelopoiesis, including the accumulation of CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) that have the potential to promote tumor growth. However, the identity, growth and migration of tumor-associated MDSCs remain undefined. We demonstrate herein that MDSCs at tumor site were primarily composed of bone marrow- (BM-) derived CD11b+Gr-1hiLy-6Cint neutrophils and CD11b+Gr-1int/dullLy-6Chi macrophages. Unexpectedly, in vivo BrdU labeling and parabiosis experiments revealed that tumor-infiltrating macrophages were replenished more rapidly than neutrophils. CCR2 deficiency caused striking conversion of infiltrating cellular dominance from macrophages to neutrophils in the tumor with the excessive production of CXCR2 ligands and granulocyte-colony stimulating factor (G-CSF) in the tumor without affecting tumor growth. Overall, our data established the identity and dynamics of MDSCs in a tumor-bearing host mediated by chemokines, as well as elucidated unexpected effects of the paucity of macrophages on tumor development.
