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

Wenji Piao (), Long Wu, Yanbao Xiong, Gregory C. Zapas, Christina M. Paluskievicz, Robert S. Oakes, Sarah M. Pettit, Margaret L. Sleeth, Keli L. Hippen, Jessica Schmitz, Philipp Ivanyi, Amol C. Shetty, Yang Song, Dejun Kong, Young Lee, Lushen Li, Marina W. Shirkey, Allison Kensiski, Aamna Alvi, Kevin Ho, Vikas Saxena, Jan H. Bräsen, Christopher M. Jewell, Bruce R. Blazar, Reza Abdi and Jonathan S. Bromberg ()
Additional contact information
Wenji Piao: University of Maryland School of Medicine
Long Wu: University of Maryland School of Medicine
Yanbao Xiong: University of Maryland School of Medicine
Gregory C. Zapas: University of Maryland School of Medicine
Christina M. Paluskievicz: University of Maryland School of Medicine
Robert S. Oakes: University of Maryland
Sarah M. Pettit: University of Maryland School of Medicine
Margaret L. Sleeth: University of Minnesota
Keli L. Hippen: University of Minnesota
Jessica Schmitz: Hannover Medical School
Philipp Ivanyi: Hannover Medical School
Amol C. Shetty: University of Maryland School of Medicine
Yang Song: University of Maryland School of Medicine
Dejun Kong: University of Maryland School of Medicine
Young Lee: University of Maryland School of Medicine
Lushen Li: University of Maryland School of Medicine
Marina W. Shirkey: University of Maryland School of Medicine
Allison Kensiski: University of Maryland School of Medicine
Aamna Alvi: University of Maryland School of Medicine
Kevin Ho: University of Maryland School of Medicine
Vikas Saxena: University of Maryland School of Medicine
Jan H. Bräsen: Hannover Medical School
Christopher M. Jewell: University of Maryland
Bruce R. Blazar: University of Minnesota
Reza Abdi: Harvard Medical School
Jonathan S. Bromberg: University of Maryland School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54874-y

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