Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma

Cancer Res. 2012 Aug 15;72(16):3967-76. doi: 10.1158/0008-5472.CAN-12-0851. Epub 2012 Jun 14.


Although it has been shown that chemoradiotherapy may induce immunogenic cell death, which could trigger T-cell immunity mediated by high-mobility group box 1 protein (HMGB1) and calreticulin, there is still limited information to support this theory directly in a clinical setting. In the present study, we evaluated antigen-specific T-cell responses against six cancer-testis antigens in peripheral blood lymphocytes from patients with esophageal squamous cell carcinoma (ESCC) receiving chemoradiation. Expression of HMGB1 and calreticulin within tumor microenvironment was also analyzed in resected samples with and without chemoradiotherapy in relation to patients survival. Tumor antigen-specific T-cell responses were confirmed in six (38%) of 16 patients with ESCC after chemoradiotherapy coexisting with elevated serum HMGB1. In addition, HMGB1 within tumor microenvironment was significantly upregulated in patients with ESCC with preoperative chemoradiotherapy, but not in those without chemoradiotherapy, and the degree of HMGB1 positively correlated with patient survival (n=88). Both irradiation and chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in nine ESCC cell lines. Furthermore, HMGB1 was able to induce maturation of dendritic cells. Together, our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses, and HMGB1 production is related to clinical outcome after chemoradiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • COS Cells
  • Calreticulin / biosynthesis
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / radiotherapy*
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cell Death / radiation effects
  • Chemoradiotherapy
  • Chlorocebus aethiops
  • Epitopes, T-Lymphocyte / immunology
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / immunology
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / radiotherapy*
  • Esophageal Squamous Cell Carcinoma
  • Female
  • HMGB1 Protein / biosynthesis
  • Humans
  • Male
  • Middle Aged
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / radiation effects
  • Transfection
  • Up-Regulation / drug effects
  • Up-Regulation / radiation effects


  • Calreticulin
  • Epitopes, T-Lymphocyte
  • HMGB1 Protein