Lower expression level of IL-33 is associated with poor prognosis of pulmonary adenocarcinoma

PLoS One. 2018 Mar 2;13(3):e0193428. doi: 10.1371/journal.pone.0193428. eCollection 2018.


Objective: Lung cancer is one of the deadliest malignancies. The immune checkpoint-blockade (ICB) tumor therapy has led to striking improvement of long-term survival for some lung cancer patients. However, the response rate of immunotherapy is still low for lung cancer. Studying the tumor microenvironment (TME) should shed light on improvement of immunotherapy of lung cancer. Interleukin-33 (IL-33), an "alarmin" cytokine, has been implicated in tumor associated immune responses and inflammatory diseases of the lung. The role of IL-33 in lung cancer progression, however, remains elusive. This study is designed to characterize IL-33 expression in lung tumor tissues and establish the clinical significance of IL-33 in non-small cell lung cancer lung cancer (NSCLC).

Materials and methods: Tumor tissue specimens from patients suffering from NSCLC were analyzed for expression of IL-33 protein by immunohistochemistry and expression of IL-33 and ST2 mRNA by RT-quantitative PCR (RT-QPCR). The expression data were analyzed for their association with clinical and pathological parameters of NSCLC. In addition, the association between expression levels of IL-33 mRNA and patient survival was determined using 5 independent expression profiling datasets of human lung cancer.

Results and conclusion: The expression levels of IL-33 and ST2 were significantly down-regulated in both adenocarcinoma and squamous cell carcinoma of the lung when compared to adjacent normal lung tissues. In addition, the level of IL-33 protein was inversely correlated with tumor grade and size. Moreover, analysis of TCGA and GEO lung cancer expression datasets revealed that higher expression levels of IL-33 mRNA were correlated with longer overall survival of patients suffering from adenocarcinoma of the lung. These data indicate that the expression levels of IL-33 are inversely associated with lung cancer progression, consistent with the hypothesis that IL-33 is involved in immune surveillance of NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Down-Regulation
  • Female
  • Humans
  • Immunohistochemistry
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Real-Time Polymerase Chain Reaction
  • Survival Rate


  • IL1RL1 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33