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

Author

Listed:
  • Wenji Piao

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Long Wu

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Yanbao Xiong

    (University of Maryland School of Medicine
    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
    University of Maryland School of Medicine)

  • Lushen Li

    (University of Maryland School of Medicine
    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
    University of Maryland School of Medicine
    University of Maryland
    University of Maryland School of Medicine)

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.

Suggested Citation

  • 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, 2024. "Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54874-y
    DOI: 10.1038/s41467-024-54874-y
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    References listed on IDEAS

    as
    1. Wenji Piao & Yanbao Xiong & Konrad Famulski & C. Colin Brinkman & Lushen Li & Nicholas Toney & Chelsea Wagner & Vikas Saxena & Thomas Simon & Jonathan S. Bromberg, 2018. "Regulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. C. Colin Brinkman & Daiki Iwami & Molly K. Hritzo & Yanbao Xiong & Sarwat Ahmad & Thomas Simon & Keli L. Hippen & Bruce R. Blazar & Jonathan S. Bromberg, 2016. "Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration," Nature Communications, Nature, vol. 7(1), pages 1-16, November.
    Full references (including those not matched with items on IDEAS)

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