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

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.