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; Jonathan S. Bromberg

doi:10.1038/s41467-024-54874-y

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 HoVikas Saxena, Jan H. Bräsen, Christopher M. Jewell, Bruce R. Blazar, Reza Abdi, Jonathan S. Bromberg

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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.

Original language	English (US)
Article number	10468
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-54874-y
State	Published - Dec 2024

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© The Author(s) 2024.

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Piao, W., Wu, L., Xiong, Y., Zapas, G. C., Paluskievicz, C. M., Oakes, R. S., Pettit, S. M., Sleeth, M. L., Hippen, K. L., Schmitz, J., Ivanyi, P., Shetty, A. C., Song, Y., Kong, D., Lee, Y., Li, L., Shirkey, M. W., Kensiski, A., Alvi, A., ... Bromberg, J. S. (2024). Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling. Nature communications, 15(1), Article 10468. https://doi.org/10.1038/s41467-024-54874-y

Piao, W, Wu, L, Xiong, Y, Zapas, GC, Paluskievicz, CM, Oakes, RS, Pettit, SM, Sleeth, ML , Hippen, KL, Schmitz, J, Ivanyi, P, Shetty, AC, Song, Y, Kong, D, Lee, Y, Li, L, Shirkey, MW, Kensiski, A, Alvi, A, Ho, K, Saxena, V, Bräsen, JH, Jewell, CM, Blazar, BR, Abdi, R & Bromberg, JS 2024, 'Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling', Nature communications, vol. 15, no. 1, 10468. https://doi.org/10.1038/s41467-024-54874-y

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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.",

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doi = "10.1038/s41467-024-54874-y",

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AU - Piao, Wenji

AU - Wu, Long

AU - Xiong, Yanbao

AU - Zapas, Gregory C.

AU - Paluskievicz, Christina M.

AU - Oakes, Robert S.

AU - Pettit, Sarah M.

AU - Sleeth, Margaret L.

AU - Hippen, Keli L.

AU - Schmitz, Jessica

AU - Ivanyi, Philipp

AU - Shetty, Amol C.

AU - Song, Yang

AU - Kong, Dejun

AU - Lee, Young

AU - Li, Lushen

AU - Shirkey, Marina W.

AU - Kensiski, Allison

AU - Alvi, Aamna

AU - Ho, Kevin

AU - Saxena, Vikas

AU - Bräsen, Jan H.

AU - Jewell, Christopher M.

AU - Blazar, Bruce R.

AU - Abdi, Reza

AU - Bromberg, Jonathan S.

PY - 2024/12

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N2 - 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.

AB - 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.

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

Abstract

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