TY - JOUR
T1 - Necroptosis in esophageal squamous cell carcinoma
T2 - An independent prognostic factor and its correlation with tumor-infiltrating lymphocytes
AU - Yamauchi, Takuro
AU - Fujishima, Fumiyoshi
AU - Hashimoto, Masatoshi
AU - Tsunokake, Junichi
AU - Akaishi, Ryujiro
AU - Gokon, Yusuke
AU - Ueki, Shunsuke
AU - Ozawa, Yohei
AU - Fukutomi, Toshiaki
AU - Okamoto, Hiroshi
AU - Sato, Chiaki
AU - Taniyama, Yusuke
AU - Nakamura, Tomohiro
AU - Nakaya, Naoki
AU - Kamei, Takashi
AU - Sasano, Hironobu
N1 - Funding Information:
Funding: This research was funded by KAKENHI grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, 18K16296.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Esophageal squamous cell carcinoma
KW - Mixed lineage kinase domain-like protein
KW - Necroptosis
KW - Neoadjuvant chemotherapy
KW - Phosphorylated mixed lineage kinase domain-like protein
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U2 - 10.3390/cancers13174473
DO - 10.3390/cancers13174473
M3 - Article
AN - SCOPUS:85114254214
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 17
M1 - 4473
ER -
