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ST2 Signaling in the Tumor Microenvironment

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 1240)

Abstract

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.

Keywords

  • ST2
  • ST2L
  • sST2
  • IL-33
  • Alternative splicing
  • Vesicle trafficking
  • Inflammatory cytokines/chemokines
  • Inflammatory gene transcription
  • Th2 lymphocytes
  • Macrophage polarization
  • Tumor microenvironment
  • Anti-IL33 neutralizing antibody
  • ST2 neutralizing antibody
  • sST2 recombinant protein
  • Immunotherapy

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Fig. 7.1
Fig. 7.2
Fig. 7.3
Fig. 7.4

Abbreviations

IL-33:

Interleukin-33

NF-kB:

Nuclear factor kappa-B

NSCLC:

Non-small cell lung cancer

sST2:

Soluble ST2

ST2:

Suppression of tumorigenicity 2/interleukin-1 receptor-like 1

ST2L:

Transmembrane form of ST2

TAM:

Tumor-associated macrophages

TLRs:

Toll-like receptors

TME:

Tumor microenvironment

Treg:

Regulatory T cells

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Chang, CP., Hu, MH., Hsiao, YP., Wang, YC. (2020). ST2 Signaling in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1240. Springer, Cham. https://doi.org/10.1007/978-3-030-38315-2_7

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