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

Takashi Kanemura, Hiroshi Miyata, Tomoki Makino, Koji Tanaka, Keijiro Sugimura, Mika Hamada-Uematsu, Yu Mizote, Hiroaki Uchida, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Hisashi Wada, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Hideaki Tahara

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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.

Original languageEnglish
Pages (from-to)3393-3402
Number of pages10
JournalCancer Science
Volume109
Issue number11
DOIs
Publication statusPublished - Nov 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Kanemura, T., Miyata, H., Makino, T., Tanaka, K., Sugimura, K., Hamada-Uematsu, M., Mizote, Y., Uchida, H., Miyazaki, Y., Takahashi, T., Kurokawa, Y., Yamasaki, M., Wada, H., Nakajima, K., Takiguchi, S., Mori, M., Doki, Y., & Tahara, H. (2018). Immunoregulatory influence of abundant MFG-E8 expression by esophageal cancer treated with chemotherapy. Cancer Science, 109(11), 3393-3402. https://doi.org/10.1111/cas.13785