气候变化领域集成服务门户(CCPortal): CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation

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DOI	10.1073/pnas.2024171118
	CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation
	Yin W.; Li Y.; Song Y.; Zhang J.; Wu C.; Chen Y.; Miao Y.; Lin C.; Lin Y.; Yan D.; Chen J.; He R.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. Ccrl2−/− mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8+ T cells or macrophages eliminates the difference in tumor growth between WT and Ccrl2−/− mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, Tlr4−/− mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antitumor T-cell immunity; CCRL2; TLR4; Tumor associated macrophages
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179839
作者单位	Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Department of Laboratory Animal Science, Fudan University, Shanghai, 200032, China; Division of Computational Biomedicine, Boston University, School of Medicine, Boston, MA 02118, United States; Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China; State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
推荐引用方式 GB/T 7714	Yin W.,Li Y.,Song Y.,et al. CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation[J],2021,118(16).
APA	Yin W..,Li Y..,Song Y..,Zhang J..,Wu C..,...&He R..(2021).CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Yin W.,et al."CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).