美国纪念斯隆凯特琳癌症中心Vinod P. Balachandran团队近期取得重要工作进展，他们研究提出，IL-33激活的ILC2诱导胰腺癌中三级淋巴样结构的形成。相关研究成果2025年1月15日在线发表于《自然》杂志上。

据介绍，三级淋巴结构（TLS）是新生的异位淋巴聚集体，在包括肿瘤在内的慢性炎症组织中调节免疫。尽管TLS的形成源于炎症触发的淋巴毒素（LT）-淋巴毒素β受体（LTβR）通路的激活，但诱导TLS的炎症信号和细胞尚未完全明确。

研究人员发现，白细胞介素-33（IL-33）可诱导 TLS的形成。在小鼠中，Il33基因缺失会显著减弱结肠炎和胰腺导管腺癌（PDAC）模型中由炎症及 LTβR 激活所诱导的TLS形成。在PDAC中，IL-33的损伤相关分子模式结构域激活表达LT的2型天然淋巴细胞（ILC2），这些细胞与假定的LTβR+髓系组织者细胞相互作用，启动三级淋巴组织生成。具有淋巴组织生成能力的ILC2从肠道迁移至PDAC，可被募集到不同组织的PDAC中，并且受到肠道微生物群的调节。

此外，研究人员在人类PDAC的TLS中检测到假定的具有淋巴组织生成能力的ILC2和表达IL-33的细胞，它们与预后改善相关。为了利用这一淋巴组织生成通路进行免疫治疗，研究人员设计了一种重组人IL-33蛋白，该蛋白可扩增肿瘤内具有淋巴组织生成能力的ILC2和TLS，并在PDAC小鼠中显示出增强的抗肿瘤活性。

总之，这一研究确定了诱导炎症触发的TLS形成的可成药通路中的分子和细胞。更广泛地说，该研究揭示了损伤相关分子模式和ILC2在淋巴组织生成方面的功能。

附：英文原文

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

Author: 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., Gnen, 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.

Issue&Volume: 2025-01-15

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.

DOI: 10.1038/s41586-024-08426-5

Source:https://www.nature.com/articles/s41586-024-08426-5