IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer

Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)–LTβ receptor (LTβR) pathway 1 , the inflammatory signals and cell...

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Vydané v:	Nature (London) Ročník 638; číslo 8052; s. 1076 - 1084
Hlavní autori:	Amisaki, Masataka, Zebboudj, Abderezak, Yano, Hiroshi, Zhang, Siqi Linsey, Payne, George, Chandra, Adrienne Kaya, Yu, Rebecca, Guasp, Pablo, Sethna, Zachary M., Ohmoto, Akihiro, Rojas, Luis A., Cheng, Charlotte, Waters, Theresa, Solovyov, Alexander, Martis, Stephen, Doane, Ashley S., Reiche, Charlotte, Bruno, Emmanuel M., Milighetti, Martina, Soares, Kevin, Odgerel, Zagaa, Moral, John Alec, Zhao, Julia N., Gönen, Mithat, Gardner, Rui, Tumanov, Alexei V., Khan, Abdul G., Vergnolle, Olivia, Nyakatura, Elisabeth K., Lorenz, Ivo C., Baca, Manuel, Patterson, Erin, Greenbaum, Benjamin, Artis, David, Merghoub, Taha, Balachandran, Vinod P.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 27.02.2025 Nature Publishing Group
Predmet:	13/51 14/19 14/63 38/39 38/91 45/91 631/250/2504/2506 631/250/580 631/67/1504/1713 64/110 64/60 96/31 Adenocarcinoma Alarmins - immunology Alarmins - metabolism Animals Antigens Carcinoma, Pancreatic Ductal - immunology Carcinoma, Pancreatic Ductal - pathology Carcinoma, Pancreatic Ductal - therapy Colitis Colitis - immunology Colitis - pathology Female Humanities and Social Sciences Humans Immunity (Disease) Immunity, Innate Immunotherapy Inflammation Inflammation - immunology Inflammation - pathology Inflammatory bowel disease Interleukin-33 - deficiency Interleukin-33 - genetics Interleukin-33 - immunology Interleukin-33 - metabolism Intestinal microflora Lymphocytes - cytology Lymphocytes - immunology Lymphoid cells Lymphotoxin Male Medical prognosis Mice Mice, Inbred C57BL multidisciplinary Pancreatic cancer Pancreatic Neoplasms - immunology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - therapy Recombinant Proteins - immunology Science Science (multidisciplinary) Tertiary Lymphoid Structures - immunology Tertiary Lymphoid Structures - pathology Toxins Tumors
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)–LTβ receptor (LTβR) pathway 1 , the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues 2 , induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LTβR-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LTβR + myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s. IL-33 induces tertiary lymphoid structures.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-024-08426-5