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

Masataka Amisaki, Abderezak Zebboudj, Hiroshi Yano, Siqi Linsey Zhang, George Payne, Adrienne Kaya Chandra, Rebecca Yu, Pablo Guasp, Zachary M. Sethna, Akihiro Ohmoto, Luis A. Rojas, Charlotte Cheng, Theresa Waters, Alexander Solovyov, Stephen Martis, Ashley S. Doane, Charlotte Reiche, Emmanuel M. Bruno, Martina Milighetti, Kevin Soares, Zagaa Odgerel, John Alec Moral, Julia N. Zhao, Mithat Gönen, Rui Gardner, Alexei V. Tumanov, Abdul G. Khan, Olivia Vergnolle, Elisabeth K. Nyakatura, Ivo C. Lorenz, Manuel Baca, Erin Patterson, Benjamin Greenbaum, David Artis, Taha Merghoub and Vinod P. Balachandran ()
Additional contact information
Masataka Amisaki: Memorial Sloan Kettering Cancer Center
Abderezak Zebboudj: Memorial Sloan Kettering Cancer Center
Hiroshi Yano: Weill Cornell Medicine
Siqi Linsey Zhang: Memorial Sloan Kettering Cancer Center
George Payne: Memorial Sloan Kettering Cancer Center
Adrienne Kaya Chandra: Memorial Sloan Kettering Cancer Center
Rebecca Yu: Memorial Sloan Kettering Cancer Center
Pablo Guasp: Memorial Sloan Kettering Cancer Center
Zachary M. Sethna: Memorial Sloan Kettering Cancer Center
Akihiro Ohmoto: Memorial Sloan Kettering Cancer Center
Luis A. Rojas: Memorial Sloan Kettering Cancer Center
Charlotte Cheng: Memorial Sloan Kettering Cancer Center
Theresa Waters: Memorial Sloan Kettering Cancer Center
Alexander Solovyov: Memorial Sloan Kettering Cancer Center
Stephen Martis: Memorial Sloan Kettering Cancer Center
Ashley S. Doane: Memorial Sloan Kettering Cancer Center
Charlotte Reiche: Memorial Sloan Kettering Cancer Center
Emmanuel M. Bruno: Memorial Sloan Kettering Cancer Center
Martina Milighetti: Memorial Sloan Kettering Cancer Center
Kevin Soares: Memorial Sloan Kettering Cancer Center
Zagaa Odgerel: Memorial Sloan Kettering Cancer Center
John Alec Moral: Memorial Sloan Kettering Cancer Center
Julia N. Zhao: Memorial Sloan Kettering Cancer Center
Mithat Gönen: Memorial Sloan Kettering Cancer Center
Rui Gardner: Memorial Sloan Kettering Cancer Center
Alexei V. Tumanov: University of Texas Health Science Center at San Antonio
Abdul G. Khan: Tri-Institutional Therapeutics Discovery Institute
Olivia Vergnolle: Tri-Institutional Therapeutics Discovery Institute
Elisabeth K. Nyakatura: Tri-Institutional Therapeutics Discovery Institute
Ivo C. Lorenz: Tri-Institutional Therapeutics Discovery Institute
Manuel Baca: Tri-Institutional Therapeutics Discovery Institute
Erin Patterson: Memorial Sloan Kettering Cancer Center
Benjamin Greenbaum: Memorial Sloan Kettering Cancer Center
David Artis: Weill Cornell Medicine
Taha Merghoub: Weill Cornell Medical College
Vinod P. Balachandran: Memorial Sloan Kettering Cancer Center

Nature, 2025, vol. 638, issue 8052, 1076-1084

Abstract: Abstract 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) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08426-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:638:y:2025:i:8052:d:10.1038_s41586-024-08426-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08426-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().