Notch Signaling Determines the M1 versus M2 Polarization of Macrophages in Antitumor Immune Responses
| Autor: | Xing-Bin Hu, Hua Han, Fei He, Ying-Min Liang, Min-Hua Zheng, Yao-Chun Wang, Lei Feng, Liang Liang, Fan Feng, Guang-Ying Dong, Xiao-Wei Liu, Hong-Yan Qin |
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| Rok vydání: | 2010 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Cell signaling Immunoblotting Melanoma Experimental Notch signaling pathway Macrophage polarization Enzyme-Linked Immunosorbent Assay Mice Transgenic Biology Nitric Oxide Immunoenzyme Techniques Carcinoma Lewis Lung Mice Cell Line Tumor Animals Humans Macrophage RNA Messenger SOCS3 Receptors Notch Reverse Transcriptase Polymerase Chain Reaction Macrophages Macrophage Activation Flow Cytometry Interleukin-10 Cell biology Interleukin 10 Oncology Immunoglobulin J Recombination Signal Sequence-Binding Protein Immunology Interleukin 12 Signal transduction Signal Transduction |
| Zdroj: | Cancer Research. 70:4840-4849 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-0269 |
| Popis: | Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch signaling showed TAM phenotypes. Forced activation of Notch signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J–mediated Notch signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch signaling. Cancer Res; 70(12); 4840–9. ©2010 AACR. |
| Databáze: | OpenAIRE |
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