High blood levels of soluble OX40 (CD134), an immune costimulatory molecule, indicate reduced survival in patients with advanced colorectal cancer

Oncol Rep. 2019 Nov;42(5):2057-2064. doi: 10.3892/or.2019.7304. Epub 2019 Sep 6.


The interaction between tumor necrosis factor receptor superfamily, member 4 (OX40) on T cells and the OX40 ligand (OX40L) on antigen‑presenting cells (APCs) is a pivotal step for T‑cell activation and the promotion of antitumor immunity. However, it is hypothesized that soluble OX40 (sOX40) in blood suppresses T‑cell activation by blocking the OX40/OX40L interaction. In the present study, the association between blood sOX40 levels and the clinical characteristics of advanced colorectal cancer (CRC) patients was investigated. Blood was collected from 22 patients with advanced CRC. Blood sOX40 levels were determined by enzyme‑linked immunosorbent assay (ELISA). Messenger RNA (mRNA) expression encoding OX40 or cytokines was analyzed by quantitative RT‑PCR. Blood sOX40 levels were positively correlated with the blood levels of carbohydrate antigen (CA) 19‑9, carcinoembryonic antigen (CEA), C‑reactive protein (CRP) and soluble programmed cell death ligand‑1 (PD‑L1) in patients but negatively correlated with the blood levels of albumin. Blood sOX40 levels were not correlated with the mRNA expression of interferon (IFN)‑gamma, interleukin (IL)‑6, IL‑10 and IL‑4 in the peripheral blood mononuclear cells (PBMCs) of the patients and were not correlated with the frequency of programmed cell death‑1 (PD‑1) expressing CD4+, CD8+ and CD56+ cells. Notably, according to both univariate and multivariate analyses, high blood sOX40 levels were significantly correlated with a reduced survival time in patients. Although activated Jurkat cells (a human T cell line) exhibited an upregulation of sOX40 production and OX40 mRNA expression, the OX40 mRNA expression of the PBMCs of patients was not correlated with blood sOX40 levels. High blood levels of sOX40 were correlated with a reduced survival time in patients with advanced CRC, possibly associated with the suppression of antitumor immunity by sOX40.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Tumor-Associated, Carbohydrate / blood
  • C-Reactive Protein / metabolism
  • Carcinoembryonic Antigen / blood
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Jurkat Cells
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Organothiophosphorus Compounds / blood
  • Receptors, OX40 / blood*
  • Receptors, OX40 / genetics*
  • Serum Albumin, Human / metabolism
  • Survival Analysis
  • Up-Regulation*


  • Antigens, Tumor-Associated, Carbohydrate
  • Carcinoembryonic Antigen
  • Organothiophosphorus Compounds
  • Receptors, OX40
  • TNFRSF4 protein, human
  • carbohydrate antigen 199, human
  • C-Reactive Protein
  • phosfolan
  • Serum Albumin, Human