美国俄勒冈健康与科学大学Naoki Oshimori团队发现，癌症干细胞在大型瘤体内释放白细胞介素-33，来促进巨噬细胞前体的免疫抑制分化。这一研究成果于2024年7月29日在线发表在国际学术期刊《免疫》。

研究人员表示，在鳞状细胞癌（SCC）中，响应白细胞介素（IL）-33的巨噬细胞创建了一个富含TGF-β的基质微环境，这个环境维持了癌症干细胞（CSC），这些干细胞部分通过激活NRF2抗氧化程序逃避了化疗引起的凋亡。

研究人员探讨了来自CSC的IL-33如何促进免疫抑制微环境的形成。具有高NRF2活性的CSC将核内IL-33重新分布到细胞质，并将IL-33作为大型癌小体（LO）的载体释放。机制上，NRF2增加了脂质重新分布酶ATG9B的表达，暴露了LO表面上的“吃我”信号，从而导致了annexin A1（ANXA1）的加载。

这些LO促进了AXNA1受体⁺髓系前体细胞向免疫抑制性巨噬细胞的分化。阻断ATG9B的重新分布酶活性或耗竭ANXA1减少了基质巨噬细胞的数量，并阻碍了肿瘤的进展。因此，IL-33通过LO从活的CSC中释放，促进了替代激活的巨噬细胞的分化，这可能与其他炎症和组织修复的背景有关。

附：英文原文

Title: Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors

Author: Hannah L. Erickson, Sachiko Taniguchi, Anish Raman, Justin J. Leitenberger, Sanjay V. Malhotra, Naoki Oshimori

Issue&Volume: 2024-07-29

Abstract: In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 createa TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-inducedapoptosis in part via activation of the NRF2 antioxidant program. Here, we examinedhow IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment.CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and releasedIL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expressionof the lipid scramblase ATG9B, which exposed an “eat me” signal on the LO surface,leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B’s scramblaseactivity or depleting ANXA1 decreased niche macrophages and hindered tumor progression.Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternativelyactivated macrophage, with potential relevance to other settings of inflammation andtissue repair.

DOI: 10.1016/j.immuni.2024.07.004

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00353-4