Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses.
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.
Wang
Yao-Chun
YC
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
He
Fei
F
Feng
Fan
F
Liu
Xiao-Wei
XW
Dong
Guang-Ying
GY
Qin
Hong-Yan
HY
Hu
Xing-Bin
XB
Zheng
Min-Hua
MH
Liang
Liang
L
Feng
Lei
L
Liang
Ying-Min
YM
Han
Hua
H
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D012333:RNA, Messenger; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D016753:Interleukin-10; D009569:Nitric Oxide