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

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

Authors

Wenji Piao^#^{1

2}, Long Wu^#^{3

4}, Yanbao Xiong^#^{3

4}, Gregory C Zapas^#⁴, Christina M Paluskievicz³, Robert S Oakes⁵, Sarah M Pettit⁴, Margaret L Sleeth⁶, Keli L Hippen⁶, Jessica Schmitz⁷, Philipp Ivanyi⁸, Amol C Shetty⁹, Yang Song⁹, Dejun Kong⁴, Young Lee^{3

4}, Lushen Li^{3

4}, Marina W Shirkey⁴, Allison Kensiski⁴, Aamna Alvi⁴, Kevin Ho⁴, Vikas Saxena⁴, Jan H Bräsen⁷, Christopher M Jewell⁵, Bruce R Blazar⁶, Reza Abdi¹⁰, Jonathan S Bromberg^{11

12

13

14}

Affiliations

¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. [email protected].
² Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. [email protected].
³ Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
⁴ Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
⁵ Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, 20742, USA.
⁶ Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, 55455, USA.
⁷ Institute for Pathology, Hannover Medical School, 30625, Hannover, Germany.
⁸ Department of Hematology and Oncology, Hannover Medical School, 30625, Hannover, Germany.
⁹ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
¹⁰ Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹¹ Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. [email protected].
¹² Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. [email protected].
¹³ Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, 20742, USA. [email protected].
¹⁴ Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Cell Communication / immunology
Cell Line, Tumor
Endothelial Cells* / immunology
Endothelial Cells* / metabolism
Humans
Lymphatic Metastasis
Lymphotoxin alpha1, beta2 Heterotrimer / metabolism
Lymphotoxin beta Receptor* / genetics
Lymphotoxin beta Receptor* / metabolism
Lymphotoxin-alpha* / metabolism
Melanoma, Experimental* / immunology
Melanoma, Experimental* / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B* / metabolism
Signal Transduction*
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / metabolism

Substances

Lymphotoxin beta Receptor
NF-kappa B
Lymphotoxin-alpha
Lymphotoxin alpha1, beta2 Heterotrimer
Ltbr protein, mouse

Abstract

MeSH terms

Substances

Grants and funding