title: Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy.
abstract: Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre- and post-treatment biopsy specimens of 30 ESCC patients and 121 pre-treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-activation associated genes such as IFNG, PRF1, and GZMB, were found in post-treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-activated cases, designating them as I-type, from other cases. However, despite the better CR rate in the I-type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-type was significantly better than that of the CDH2-positive cases in the I-type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested to cooperatively enhance the effect of CRT in the CDH2-negative I-type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics.
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Aoyagi
authors.affiliation: Department of Clinical Trial Promotion, Chiba Cancer Center, Chiba, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Minashi
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Komatsuzaki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Chiwaki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tamaoki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Gastrointestinal Oncology and Endoscopy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Oda
authors.affiliation: Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Narumi
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Therapeutic Oncology, Kyoto University, Kyoto, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D059248:Chemoradiotherapy; D058750:Epithelial-Mesenchymal Transition; D004938:Esophageal Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D008875:Middle Aged; D055502:Secondary Prevention; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059467:Transcriptome