Necroptosis in Esophageal Squamous Cell Carcinoma: An Independent Prognostic Factor and Its Correlation with Tumor-Infiltrating Lymphocytes

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 res...

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Bibliographic Details
Published in:Cancers 2021-09, Vol.13 (17), p.4473
Main Authors: Yamauchi, Takuro, Fujishima, Fumiyoshi, Hashimoto, Masatoshi, Tsunokake, Junichi, Akaishi, Ryujiro, Gokon, Yusuke, Ueki, Shunsuke, Ozawa, Yohei, Fukutomi, Toshiaki, Okamoto, Hiroshi, Sato, Chiaki, Taniyama, Yusuke, Nakamura, Tomohiro, Nakaya, Naoki, Kamei, Takashi, Sasano, Hironobu
Format: Article
Language:English
Subjects:
Antibodies
Antigens
Apoptosis
Biopsy
CD3 antigen
CD8 antigen
Cell death
Chemoresistance
Chemotherapy
Esophageal cancer
Esophagus
Forkhead protein
Foxp3 protein
Kinases
Lymphatic system
Lymphocytes
MAP kinase
Medical prognosis
Metastases
Multivariate analysis
Necroptosis
Patients
Plasma
Squamous cell carcinoma
Surgery
Tumor microenvironment
Tumor-infiltrating lymphocytes
Tumorigenesis
Tumors
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13174473