Immunoregulatory influence of abundant MFG-E8 expression by esophageal cancer treated with chemotherapy

Cancer Sci. 2018 Nov;109(11):3393-3402. doi: 10.1111/cas.13785. Epub 2018 Sep 22.

Abstract

Milk fat globule-epidermal growth factor factor 8 (MFG-E8) is secreted from macrophages and is known to induce immunological tolerance mediated by regulatory T cells. However, the roles of the MFG-E8 that is expressed by cancer cells have not yet been fully examined. Expression of MFG-E8 was examined using immunohistochemistry in surgical samples from 134 patients with esophageal squamous cell carcinoma. The relationships between MFG-E8 expression levels and clinicopathological factors, including tumor-infiltrating lymphocytes, were evaluated. High MFG-E8 expression was observed in 23.9% of the patients. The patients with tumors highly expressing MFG-E8 had a significantly higher percentage of neoadjuvant chemotherapy (NAC) history (P < .0001) and shorter relapse-free survival (P = 0.012) and overall survival (OS; P = .0047). On subgroup analysis, according to NAC history, patients with high MFG-E8 expression had significantly shorter relapse-free survival (P = .027) and OS (P = .0039) only when they had been treated with NAC. Furthermore, tumors with high MFG-E8 expression had a significantly lower ratio of CD8+ T cells/regulatory T cells in tumor-infiltrating lymphocytes (P = .042) only in the patients treated with NAC, and those with a lower ratio had a shorter OS (P = .026). High MFG-E8 expression was also found to be an independent prognostic factor in multivariate analysis. The abundant MFG-E8 expression in esophageal squamous cell carcinoma might have a negative influence on the long-term survival of patients after chemotherapy by affecting T-cell regulation in the tumor microenvironment.

Keywords: apoptosis; cancer microenvironment; immunological escape; neoadjuvant chemotherapy; regulatory T cell.

MeSH terms

  • Animals
  • Antigens, Surface / metabolism*
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / surgery
  • Disease-Free Survival
  • Drug Therapy / methods*
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / surgery
  • Esophageal Squamous Cell Carcinoma
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Milk Proteins / metabolism*
  • Neoadjuvant Therapy
  • Prognosis
  • Treatment Outcome
  • Tumor Microenvironment
  • Up-Regulation*

Substances

  • Antigens, Surface
  • MFGE8 protein, human
  • Milk Proteins