PLoS ONE (Jan 2015)

Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy.

  • Yosuke Tanaka,
  • Kazuhiko Aoyagi,
  • Keiko Minashi,
  • Rie Komatsuzaki,
  • Masayuki Komatsu,
  • Fumiko Chiwaki,
  • Masashi Tamaoki,
  • Takao Nishimura,
  • Naoki Takahashi,
  • Ichiro Oda,
  • Yuji Tachimori,
  • Tokuzo Arao,
  • Kazuto Nishio,
  • Shigehisa Kitano,
  • Kenta Narumi,
  • Kazunori Aoki,
  • Satoshi Fujii,
  • Atsushi Ochiai,
  • Teruhiko Yoshida,
  • Manabu Muto,
  • Yasuhide Yamada,
  • Hiroki Sasaki

DOI
https://doi.org/10.1371/journal.pone.0143804
Journal volume & issue
Vol. 10, no. 12
p. e0143804

Abstract

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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.