Nature communications · 2024
Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.