Origins of tumor-associated macrophages and neutrophils

被引:522
作者
Cortez-Retamozo, Virna [1 ,2 ]
Etzrodt, Martin [1 ,2 ]
Newton, Andita [1 ,2 ]
Rauch, Philipp J. [1 ,2 ]
Chudnovskiy, Aleksey [1 ,2 ]
Berger, Cedric [1 ,2 ]
Ryan, Russell J. H. [3 ]
Iwamoto, Yoshiko [1 ,2 ]
Marinelli, Brett [1 ,2 ]
Gorbatov, Rostic [1 ,2 ]
Forghani, Reza [1 ,2 ]
Novobrantseva, Tatiana I. [4 ]
Koteliansky, Victor [4 ]
Figueiredo, Jose-Luiz [1 ,2 ]
Chen, John W. [1 ,2 ]
Anderson, Daniel G. [5 ]
Nahrendorf, Matthias [1 ,2 ]
Swirski, Filip K. [1 ,2 ]
Weissleder, Ralph [1 ,2 ,6 ]
Pittet, Mikael J. [1 ,2 ]
机构
[1] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA
[2] Harvard Univ, Sch Med, Boston, MA 02114 USA
[3] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
[4] Alnylam Pharmaceut, Cambridge, MA 02142 USA
[5] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA
[6] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
cancer immunity; tumor microenvironment; DENDRITIC CELLS; PROGENITOR CELLS; INFLAMMATORY MONOCYTES; SUPPRESSOR-CELLS; IMMUNE-SYSTEM; CANCER; MICE; CHEMOTHERAPY; SPLENECTOMY; METASTASIS;
D O I
10.1073/pnas.1113744109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b(+) Ly-6C(hi) monocytic and CD11b(+) Ly-6G(hi) granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells.
引用
收藏
页码:2491 / 2496
页数:6
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