Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Adv Exp Med Biol. 2020;1240:83-93. doi: 10.1007/978-3-030-38315-2_7.
Suppression of tumorigenicity 2 (ST2), also known as interleukin-1 receptor-like 1 (IL1RL1), is one of the natural receptors of IL-33. Three major isoforms, ST2L (transmembrane form), sST2 (soluble form), and ST2V, are generated by alternative splicing. Damage to stromal cells induces necrosis and release of IL-33, which binds to heterodimeric ST2L/IL-1RAcP complex on the membrane of a variety of immune cells. This IL-33/ST2L signal induces transcription of the downstream inflammatory and anti-inflammatory genes by activating diverse intracellular kinases and factors to mount an adequate immune response, even in tumor microenvironment. For example, activation of IL-33/ST2L signal may trigger Th2-dependent M2 macrophage polarization to facilitate tumor progression. Notably, sST2 is a soluble form of ST2 that lacks a transmembrane domain but preserves an extracellular domain similar to ST2L, which acts as a "decoy" receptor for IL-33. sST2 has been shown to involve in the inflammatory tumor microenvironment and the progression of colorectal cancer, non-small cell lung cancer, and gastric cancer. Therefore, targeting the IL-33/ST2 axis becomes a promising new immunotherapy for treatment of many cancers. This chapter reviews the recent findings on IL-33/ST2L signaling in tumor microenvironment, the trafficking mode of sST2, and the pharmacological strategies to target IL-33/ST2 axis for cancer treatment.
肿瘤抑制因子 2（ST2），也称为白细胞介素-1 受体样 1（IL1RL1），是白细胞介素-33（IL-33）的天然受体之一。通过选择性剪接产生三种主要的同种型：ST2L（跨膜形式）、sST2（可溶性形式）和 ST2V。基质细胞的损伤会诱导坏死并释放 IL-33，后者与膜上的各种免疫细胞的异二聚体 ST2L/IL-1RAcP 复合物结合。这种 IL-33/ST2L 信号通过激活各种细胞内激酶和因子来诱导下游炎症和抗炎基因的转录，从而引发适当的免疫反应，即使在肿瘤微环境中也是如此。例如，IL-33/ST2L 信号的激活可能触发 Th2 依赖性 M2 巨噬细胞极化，从而促进肿瘤进展。值得注意的是，sST2 是 ST2 的一种可溶性形式，缺乏跨膜结构域，但保留了与 ST2L 相似的细胞外结构域，后者作为 IL-33 的“诱饵”受体发挥作用。sST2 已被证明参与炎症性肿瘤微环境以及结直肠癌、非小细胞肺癌和胃癌的进展。因此，靶向 IL-33/ST2 轴成为治疗多种癌症的有前途的新免疫疗法。本章综述了最近在肿瘤微环境中发现的 IL-33/ST2L 信号、sST2 的运输模式以及靶向 IL-33/ST2 轴治疗癌症的药理学策略。
