Sawanobori Yasushi, Ueha Satoshi, Kurachi Makoto, Shimaoka Takeshi, Talmadge James E, Abe Jun, Shono Yusuke, Kitabatake Masahiro, Kakimi Kazuhiro, Mukaida Naofumi, Matsushima Kouji
Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Blood. 2008 Jun 15;111(12):5457-66. doi: 10.1182/blood-2008-01-136895. Epub 2008 Mar 28.
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 composed primarily of bone marrow-derived CD11b(+)Gr-1(hi)Ly-6C(int) neutrophils and CD11b(+)Gr-1(int/dull)Ly-6C(hi) macrophages. Unexpectedly, in vivo bromodeoxyuridine (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 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 and elucidated unexpected effects of the paucity of macrophages on tumor development.
肿瘤生长与异常的骨髓生成相关，包括CD11b(+)Gr-1(+)髓源性抑制细胞（MDSCs）的积累，这些细胞具有促进肿瘤生长的潜力。然而，肿瘤相关MDSCs的特性、生长和迁移仍不明确。我们在此证明，肿瘤部位的MDSCs主要由骨髓来源的CD11b(+)Gr-1(高)Ly-6C(中)中性粒细胞和CD11b(+)Gr-1(中/低)Ly-6C(高)巨噬细胞组成。出乎意料的是，体内溴脱氧尿苷（BrdU）标记和联体共生实验表明，肿瘤浸润巨噬细胞的补充速度比中性粒细胞更快。CCR2缺陷导致肿瘤中浸润细胞优势从巨噬细胞显著转变为中性粒细胞，肿瘤中CXCR2配体和粒细胞集落刺激因子过度产生，但不影响肿瘤生长。总体而言，我们的数据确定了趋化因子介导的荷瘤宿主中MDSCs的特性和动态，并阐明了巨噬细胞缺乏对肿瘤发展的意外影响。
