调节性T细胞通过淋巴毒素信号通路与肿瘤细胞和内皮细胞进行串扰。

Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling.

作者信息

Piao Wenji, Wu Long, Xiong Yanbao, Zapas Gregory C, Paluskievicz Christina M, Oakes Robert S, Pettit Sarah M, Sleeth Margaret L, Hippen Keli L, Schmitz Jessica, Ivanyi Philipp, Shetty Amol C, Song Yang, Kong Dejun, Lee Young, Li Lushen, Shirkey Marina W, Kensiski Allison, Alvi Aamna, Ho Kevin, Saxena Vikas, Bräsen Jan H, Jewell Christopher M, Blazar Bruce R, Abdi Reza, Bromberg Jonathan S

机构信息

Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

出版信息

Nat Commun. 2024 Dec 2;15(1):10468. doi: 10.1038/s41467-024-54874-y.

DOI:10.1038/s41467-024-54874-y

PMID:39622857

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11612289/

Abstract

Regulatory T cells (Tregs) with multifaceted functions suppress anti-tumor immunity by signaling surrounding cells. Here we report Tregs use the surface lymphotoxin (LT)α1β2 to preferentially stimulate LT beta receptor (LTβR) nonclassical NFκB signaling on both tumor cells and lymphatic endothelial cells (LECs) to accelerate tumor growth and metastasis. Selectively targeting LTβR nonclassical NFκB pathway inhibits tumor growth and migration in vitro. Leveraging in vivo Treg LTα1β2 interactions with LTβR on tumor cells and LECs, transfer of wild type but not LTα Tregs promotes B16F10 melanoma growth and tumor cell-derived chemokines in LTβR mice; and increases SOX18 and FLRT2 in lymphatic vessels of LTβR melanoma. Blocking the nonclassical pathway suppresses tumor growth and lymphatic metastasis by reducing chemokine production, restricting Treg recruitment to tumors, and retaining intratumoral IFNγ CD8 T cells. Our data reveals that Treg LTα1β2 promotes LTβR nonclassical NFκB signaling in tumor cells and LECs providing a rational strategy to prevent Treg promoted tumor growth and metastasis.

摘要

具有多方面功能的调节性T细胞（Tregs）通过向周围细胞发出信号来抑制抗肿瘤免疫。在此，我们报告Tregs利用表面淋巴毒素（LT）α1β2优先刺激肿瘤细胞和淋巴管内皮细胞（LECs）上的LTβ受体（LTβR）非经典NFκB信号传导，以加速肿瘤生长和转移。选择性靶向LTβR非经典NFκB途径可在体外抑制肿瘤生长和迁移。利用体内Treg的LTα1β2与肿瘤细胞和LECs上的LTβR的相互作用，野生型而非LTα Tregs的转移促进了LTβR小鼠中B16F10黑色素瘤的生长和肿瘤细胞衍生的趋化因子；并增加了LTβR黑色素瘤淋巴管中的SOX18和FLRT2。阻断非经典途径可通过减少趋化因子产生、限制Tregs向肿瘤的募集以及保留肿瘤内的IFNγ CD8 T细胞来抑制肿瘤生长和淋巴转移。我们的数据表明，Treg的LTα1β2促进肿瘤细胞和LECs中的LTβR非经典NFκB信号传导，为预防Treg促进的肿瘤生长和转移提供了一种合理策略。