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Abstract
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.
Highlights
Esophageal squamous cell carcinoma (ESCC) is well known to be sensitive to radiotherapy and its combination with chemotherapy was proven to have clinical benefits [1, 2]
In study group 1, peripheral blood lymphocytes (PBL) obtained from before, during, and after chemoradiotherapy were cultured for 14 days in vitro and cultured T cells were subjected to an IFN-g enzyme-linked immunospot (ELISPOT) assay as responder cells
In summarized data from case 10 at different time points, antigen-specific T-cell responses were significantly induced against COS transfected with II mRNA– binding protein 3 (IMP3), cell division cycle associated 1 (CDCA1), TOMM34, and HIG2 in combination with HLA-A0201 during chemoradiotherapy (Fig. 1B), whereas there was no specific T-cell response before chemoradiotherapy
Summary
Esophageal squamous cell carcinoma (ESCC) is well known to be sensitive to radiotherapy and its combination with chemotherapy was proven to have clinical benefits [1, 2]. It is generally accepted that irradiation is able to directly induce apoptosis or necrosis against ESCC and various strategies of radiotherapy, such as hyperfractionated irradiation [3] and image-guided radiotherapy [4], to enhance direct cytotoxic and cytostatic effects against ESCC through radiation oncology [5, 6]. There is accumulating evidence to support the novel concept that radiotherapy with/without chemotherapy may induce immunogenic cell death, which could trigger uptake of antigenic components by dendritic cells (DC) and Authors' Affiliations: 1Department of Surgery, National University of Singapore, 2Cancer Science Institute of Singapore, Singapore; 3Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma; and 4First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
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