ST2 Signaling in the Tumor Microenvironment

Adv Exp Med Biol. 2020:1240:83-93. doi: 10.1007/978-3-030-38315-2_7.

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

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / antagonists & inhibitors
  • Interleukin-1 Receptor-Like 1 Protein / immunology
  • Interleukin-1 Receptor-Like 1 Protein / metabolism*
  • Interleukin-33 / antagonists & inhibitors
  • Interleukin-33 / immunology
  • Interleukin-33 / metabolism
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Signal Transduction* / immunology
  • Tumor Microenvironment* / immunology

Substances

  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33