Soluble interleukin‐6 receptor is a serum biomarker for the response of esophageal carcinoma to neoadjuvant chemoradiotherapy

Abstract

Preoperative chemoradiotherapy has been shown to improve the outcome of patients with esophageal cancer, but because response to this therapy varies, it is desirable to identify in advance individuals who would be unlikely to benefit, in order to avoid unnecessary adverse drug effects. The serum profiles of 84 cytokines and related proteins were determined in 37 patients with esophageal squamous cell carcinoma who received identical neoadjuvant preoperative chemoradiotherapy regimens and underwent surgical resection. Histological response to this therapy was assessed in surgically resected specimens. The serum soluble interleukin‐6 receptor (sIL6R) level was significantly higher in 30 patients who failed to achieve a histological complete response (P = 0.005). Multivariate analysis revealed that the increased level of sIL6R was one of several significant independent predictors of an unfavorable outcome (hazard ratio, 2.87; P = 0.017). The increased level of this cytokine in patients who did not obtain a complete response was reproducibly observed in an independent cohort of 34 patients. Esophageal squamous cell carcinoma patients with an increased serum level of sIL6R are predicted to respond poorly to preoperative chemoradiotherapy, therefore, their exclusion from this treatment may be considered. Persistent systemic inflammation is implicated as a possible mechanism of resistance to this therapy.

Interleukin‐6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

“…IL-6 is a representative proinflammatory cytokine. Prospective and retrospective studies have shown that serum IL-6 levels are related to the tumor stage and size, metastasis and survival of colon cancer patients, (24) chemotherapy efficacy for advanced pancreatic cancer, (25) neoadjuvant chemoradiotherapy for esophageal carcinoma, (26) advanced stage and metastasis-related morbidity of breast cancer, (27) and clinical efficacy of personalized peptide vaccination for advanced biliary tract cancer (28) and colorectal cancers. (29) Interleukin-6 is produced by various cell types, including cancer cells and cancer-associated fibroblasts because of chronic inflammation in tumor sites.…”

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

“…A previous study has reported that serum IL‐6 levels are related to the tumor stage and size, metastasis, and survival in colon cancer patients . Clinical studies have demonstrated that the IL‐6 level might be a good predictive biomarker for the clinical benefit of peptide vaccines …”

“…(10) Clinical studies have demonstrated that the IL-6 level might be a good predictive biomarker for the clinical benefit of peptide vaccines. (11,12) Previously, it was reported that IL-6 signaling suppresses MHC class II expression on murine dendritic cells through STAT3 activation and attenuates CD4 + T cell-mediated immune responses. (13,14) Furthermore, a previous study using tumor-bearing mouse models indicated that administration of a mAb antagonizing IL-6R enhances T cell responses and inhibits tumor growth in vivo.…”

Novel Candidate Biomarkers of Chemoradiosensitivity in Esophageal Squamous Cell Carcinoma: A Systematic Review

“…Secreted sIL-6R binds to IL-6, and the resultant sIL-6R/IL-6 complex evokes intracellular signaling [24]. Makuuchi et al [25] showed that the serum sIL-6R levels were significantly higher in 30 patients who failed to achieve a pathological complete response (pCR), and multivariate analysis indicated that a high sIL-6R level is one of several significant independent predictors of an unfavorable outcome after preoperative CRT followed by esophagectomy.…”