Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling
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 end...
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| Format: | Article |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54874-y |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wenji Piao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ec08d3585edd480ea839e96b3bc9f2de |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ec08d3585edd480ea839e96b3bc9f2de2025-08-20T02:20:44ZengNature PortfolioNature Communications2041-17232024-12-0115111810.1038/s41467-024-54874-yRegulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signalingWenji Piao0Long Wu1Yanbao Xiong2Gregory C. Zapas3Christina M. Paluskievicz4Robert S. Oakes5Sarah M. Pettit6Margaret L. Sleeth7Keli L. Hippen8Jessica Schmitz9Philipp Ivanyi10Amol C. Shetty11Yang Song12Dejun Kong13Young Lee14Lushen Li15Marina W. Shirkey16Allison Kensiski17Aamna Alvi18Kevin Ho19Vikas Saxena20Jan H. Bräsen21Christopher M. Jewell22Bruce R. Blazar23Reza Abdi24Jonathan S. Bromberg25Department of Surgery, University of Maryland School of MedicineDepartment of Surgery, University of Maryland School of MedicineDepartment of Surgery, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineDepartment of Surgery, University of Maryland School of MedicineFischell Department of Bioengineering, University of MarylandCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineDepartment of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of MinnesotaDepartment of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of MinnesotaInstitute for Pathology, Hannover Medical SchoolDepartment of Hematology and Oncology, Hannover Medical SchoolInstitute for Genome Sciences, University of Maryland School of MedicineInstitute for Genome Sciences, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineDepartment of Surgery, University of Maryland School of MedicineDepartment of Surgery, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineCenter for Vascular and Inflammatory Diseases, University of Maryland School of MedicineInstitute for Pathology, Hannover Medical SchoolFischell Department of Bioengineering, University of MarylandDepartment of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of MinnesotaTransplantation Research Center, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Surgery, University of Maryland School of MedicineAbstract 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.https://doi.org/10.1038/s41467-024-54874-y |
| spellingShingle | 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 Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling Nature Communications |
| title | Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling |
| title_full | Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling |
| title_fullStr | Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling |
| title_full_unstemmed | Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling |
| title_short | Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling |
| title_sort | regulatory t cells crosstalk with tumor cells and endothelium through lymphotoxin signaling |
| url | https://doi.org/10.1038/s41467-024-54874-y |
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