Immunogenic Tumor Cell Death Induced by Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma

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 ¼ 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. Cancer Res; 72(16); 3967-76. Ó2012 AACR.

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…15 Apoptosis occurs ubiquitously in normal tissues and causes 'quiet' cell death that uses phosphatidylserine (PS) as an 'eat-me' signal to be quickly recognized by peripheral APCs. Although apoptotic cell death has been historically considered to be nonimmunogenic, 16 recent studies unraveled that several antineoplastic agents, including doxorubicin, 1,17 oxaliplatin, 18,19 cisplatin, 20 and irradiation, 21,22,23 can trigger immunogenic apoptosis. 2 Mechanistically, the immunogenic apoptotic bodies induced by exposure to doxorubicin are sensed by APCs through their TLR-2/TLR-9-MyD88 signaling pathways.…”

“…However, the observation that the tumor microenvironment tends to be pro-oxidative 63 implies that a therapeutic approach using antioxidants to decrease ROS production would be favorable to stimulate antitumor immunity. Importantly, many anticancer agents, including chemotherapy, 30 radiation, 22 or oncolytic viruses, 9,64,65 have been shown to induce HMGB1 release from cancer cells, highlighting the significance of further addressing the mechanism of how these modalities affect the redox status of HMGB1.…”

Consensus guidelines for the detection of immunogenic cell death

“…22 It turned out that the unsuspected ability of doxorubicin (an anthracycline employed for the treatment of various carcinomas) to trigger ICD as a standalone intervention, hence converting dying cancer cells into a vaccine that is efficient in the absence of adjuvants, is shared by a relatively restricted set of lethal triggers. [28][29][30][31][32][33] These include, but perhaps are not limited to, mitoxantrone and epirubicin (2 other anthracyclines currently used in the clinic), [34][35][36][37] bleomycin (a glycopeptide antibiotic endowed with antineoplastic properties), 38 oxaliplatin (a platinum derivative generally employed against colorectal carcinoma), [39][40][41][42] cyclophosphamide (an alkylating agent approved for the treatment of neoplastic and autoimmune conditions), [43][44][45][46][47][48] etoposide (a topoisomerase inhibitor currently used for the treatment of several neoplasms) combined with the chemical inhibitor of glycolysis 2-deoxyglucose, 49,50 patupilone (a microtubular inhibitor that has not yet been approved for use in humans), [51][52][53] septacidin (an antifungal antibiotic produced by Streptomyces fibriatus) 54,55 specific forms of radiation therapy, 34,[56][57][58][59][60][61][62][63][64] photodynamic therapy (a clinically approved antican...…”

Increased neutrophil-to-lymphocyte ratio is a novel marker for nutrition, inflammation and chemotherapy outcome in patients with locally advanced and metastatic esophageal squamous cell carcinoma

“…The authors previously reported that malnutrition or hypoalbuminemia correlates well with immune suppression, systemic inflammation and suppression of cell-mediated immunity (34)(35)(36)(37)(38). Systemic inflammation may underlie these conditions, which are prominent in patients with advanced cancer.…”