Rubiginosin B selectively inhibits Treg cell differentiation and enhances anti-tumor immune responses by targeting calcineurin-NFAT signaling pathway

doi:10.1016/j.phymed.2023.154898

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	Rubiginosin B selectively inhibits Treg cell differentiation and enhances anti-tumor immune responses by targeting calcineurin-NFAT signaling pathway
	Geng,Chang-An; Chen,Feng-Yang; Zheng,Jing-Bin; Liao,Ping; Li,Tian-Ze; Zhang,Xue-Mei; Chen,Xin; Chen,Ji-Jun
	2023
发表期刊	PHYTOMEDICINE
ISSN	1618-095X
卷号	116 页码:154898
摘要	Background: The accumulation of CD4(+)Foxp3(+) regulatory T cells (Tregs) in the tumor microenvironment (TME) dampens anti-tumor immune responses and promotes tumor progression. Therefore, the elimination of Tregs has become a strategy to enhance the efficacy of tumor immunotherapy, although it is still a daunting challenge. Rhododendron brachypodum (R. brachypodum) is a perennial shrub mainly distributed in Southwestern China, whereas the chemical constituents in this plant remain elusive. Purpose: To identify small-molecule inhibitors of Tregs from R. brachypodum. Methods: Meroterpenoids in R. brachypodum were isolated by column chromatography under the guidance of LCMS analyses. The structures of isolates were identified by spectroscopic data and quantum calculations. The activities of compounds were first evaluated on CD4(+) T cell differentiation by flow cytometry in Th1, Th2, Th17, and Treg polarizing conditions, and then on CT26 and MC38 murine colorectal carcinoma cells-allografted mice models. The mechanism of action was first investigated by determining Foxp3 degradation in Jurkat T cells transfected with pLVX-TetOne-Puro-Foxp3-tGFP, and then through analyses of Foxp3 expression on several pre-transcriptional signaling molecules. Results: Two new prenylated phenolic acids (1 and 2) and a chromane meroterpenoid, rubiginosin B (RGB, 3) were obtained from R. brachypodum. The structure of S-anthopogochromene C (1) was rectified according to the electronic circular dichroism (ECD) experiment, and rhodobrachypodic acid (2) was proposed as the precursor of RGB by photochemical transformation. In this investigation, we first found that RGB (3) selectively suppressed the de novo differentiation of TGF beta-induced CD4(+)Foxp3(+) regulatory T cells (iTregs), overcome the immunosuppressive TME, and consequently inhibited the growth of tumor in mouse models. The mechanistic study revealed that RGB could target calcineurin, inhibited the nuclear factor of activated T cells (NFAT) dephosphorylation, and down-regulated Foxp3 expression. The hypothetical binding modes of RGB with calcineurin were predicted by molecular docking, and the interactions were mainly hydrophobic effects and hydrogen bonds. Conclusion: These results suggest that RGB enhances anti-tumor immune responses by inhibiting Treg cell differentiation through calcineurin-NFAT signaling pathway, and therefore RGB or its analogs may be used as adjuvant agents meriting further investigation.
关键词	Rubiginosin B (RGB) CD4(+)Foxp3(+) regulatory T cells (Tregs) Calcineurin Nuclear factor of activated T cells (NFAT) Tumor microenvironment Rhododendron brachypodum REGULATORY T-CELLS RHODODENDRON IMMUNOSUPPRESSION DERIVATIVES INDUCTION EXPANSION RAPAMYCIN
学科领域	Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
DOI	10.1016/j.phymed.2023.154898
收录类别	SCI
WOS记录号	WOS:001012415100001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75398
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Geng,Chang-An,Chen,Feng-Yang,Zheng,Jing-Bin,et al. Rubiginosin B selectively inhibits Treg cell differentiation and enhances anti-tumor immune responses by targeting calcineurin-NFAT signaling pathway[J]. PHYTOMEDICINE,2023,116:154898.
APA	Geng,Chang-An.,Chen,Feng-Yang.,Zheng,Jing-Bin.,Liao,Ping.,Li,Tian-Ze.,...&Chen,Ji-Jun.(2023).Rubiginosin B selectively inhibits Treg cell differentiation and enhances anti-tumor immune responses by targeting calcineurin-NFAT signaling pathway.PHYTOMEDICINE,116,154898.
MLA	Geng,Chang-An,et al."Rubiginosin B selectively inhibits Treg cell differentiation and enhances anti-tumor immune responses by targeting calcineurin-NFAT signaling pathway".PHYTOMEDICINE 116(2023):154898.

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