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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Published in:Nature (London) Vol. 638; no. 8052; pp. 1076 - 1084
Main Authors: 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.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.02.2025
Nature Publishing Group
Subjects:
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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
Online Access:Get full text
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Summary: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.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-024-08426-5