Necroptosis in esophageal squamous cell carcinoma: An independent prognostic factor and its correlation with tumor-infiltrating lymphocytes

Takuro Yamauchi, Fumiyoshi Fujishima, Masatoshi Hashimoto, Junichi Tsunokake, Ryujiro Akaishi, Yusuke Gokon, Shunsuke Ueki, Yohei Ozawa, Toshiaki Fukutomi, Hiroshi Okamoto, Chiaki Sato, Yusuke Taniyama, Tomohiro Nakamura, Naoki Nakaya, Takashi Kamei, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

Abstract

Necroptosis is a pivotal process in cancer biology; however, the clinical significance of necroptosis in esophageal squamous cell carcinoma (ESCC) has remained unknown. Therefore, in this study, we aimed to verify the potential involvement of necroptosis in the clinical outcome, chemotherapeutic resistance, and tumor microenvironment of ESCC. Mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunohistochemically examined in 88 surgically resected specimens following neoadjuvant chemotherapy (NAC) and 53 pre-therapeutic biopsy specimens, respectively. Tumor-infiltrating lymphocytes (TILs) were also evaluated by immunolocalizing CD3, CD8, and forkhead box protein 3 (FOXP3) in the residual tumors after NAC. High pMLKL status in the post-NAC resected specimens was significantly correlated with worse prognosis in ESCC patients. Multivariate analysis demonstrated that a high pMLKL status was an independent prognostic factor. In pre-NAC biopsy specimens, a high pMLKL status was significantly associated with a lower therapeutic efficacy. CD8+ TILs were significantly lower in the high-pMLKL group. FOXP3+ TILs were significantly higher in both high-MLKL and high-pMLKL groups. We first demonstrated pMLKL status as an independent prognostic factor in ESCC patients. Our study revealed the possible involvement of necroptosis in the immunosuppressive microenvironment, resulting in the attenuated therapeutic efficacy of NAC and eventual adverse clinical outcomes in ESCC.

Original languageEnglish
Article number4473
JournalCancers
Volume13
Issue number17
DOIs
Publication statusPublished - 2021 Sep

Keywords

  • Esophageal squamous cell carcinoma
  • Mixed lineage kinase domain-like protein
  • Necroptosis
  • Neoadjuvant chemotherapy
  • Phosphorylated mixed lineage kinase domain-like protein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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