Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2020; 26(31): 4656-4668
Published online Aug 21, 2020. doi: 10.3748/wjg.v26.i31.4656
Clinical and prognostic significance of CC chemokine receptor type 8 protein expression in gastrointestinal stromal tumors
Huai-Liang Li, Lin-Hua Wang, Yi-Lin Hu, Ying Feng, Xiao-Hong Li, Yi-Fei Liu, Peng Li, Qin-Sheng Mao, Wan-Jiang Xue
Huai-Liang Li, Yi-Lin Hu, Ying Feng, Peng Li, Qin-Sheng Mao, Wan-Jiang Xue, Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
Lin-Hua Wang, Department of Intensive Care Unit, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
Xiao-Hong Li, Department of Surgical Comprehensive Laboratory, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
Yi-Fei Liu, Department of Pathology, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
Author contributions: Li HL and Wang LH contributed equally to this work; Li HL wrote the paper; Wang LH performed the research; Hu YL contributed new reagents or analytic tools; Feng Y and Liu YF analyzed the data; Mao QS and Xue WJ edited the paper and provided primary revised opinion; Xue WJ designed the research.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Nantong University Affiliated Hospital.
Informed consent statement: Informed written consent was obtained from the patients for publication of this report and any accompanying images.
Conflict-of-interest statement: We have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Wan-Jiang Xue, FAASLD, BSc, MD, PhD, Chief Doctor, Professor, Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, No. 20 Xisi Street, Nantong 226001, Jiangsu Province, China.
Received: March 4, 2020
Peer-review started: March 4, 2020
First decision: April 25, 2020
Revised: June 7, 2020
Accepted: July 18, 2020
Article in press: July 18, 2020
Published online: August 21, 2020

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Surgical resection and tyrosine kinase inhibitors are defined as the main treatments but cannot cure patients with advanced GIST, which eventually develops into recurrence and acquired drug resistance. Therefore, it is necessary to identify prognostic biomarkers and new therapeutic targets for GISTs. CC chemokine receptor type 8 (CCR8) protein participates in regulation of immune responses. Recent studies on CCR8 in non-small cell lung cancer and colorectal cancer showed that it was highly expressed in tumor-infiltrating regulatory T cells and correlated with a poor prognosis.


To detect CCR8 expression in GIST tissues and analyze its relationships with clinicopathological features and prognosis in patients with GISTs.


Tissue samples were used for the tissue microarrays construction. The microarrays were then subjected to immunohistochemical analyses to detect CCR8 expression. Next, Kaplan–Meier analysis was utilized to calculate the survival rate of patients with complete follow-up data, and the potential prognostic value of CCR8 was evaluated by Cox regression analysis. Finally, a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes single-gene enrichment chart of CCR8 was constructed using the STRING database.


CCR8-positive signals were detected as brown or brown-yellow particles by immunohistochemistry located in the cytoplasm. Among 125 tissue samples, 74 had CCR8 high expression and 51 had low or negative expression. Statistical analyses suggested CCR8 was significantly correlated with tumor size, mitotic index, AFIP-Miettinen risk classification and tumor location. Kaplan–Meier and multivariate analyses showed that patients with low or negative CCR8 expression, mitotic index < 5/high-power fields (HPF) and tumor diameter < 5 cm had a better prognosis. Based on the STRING database, CCR8 was significantly enriched in biological processes such as tumor immunity, T lymphocyte chemotaxis, migration and pathways like the nuclear factor-κB and tumor necrosis factor pathways as well as intestinal immune regulation networks.


CCR8 is a prognostic biomarker for malignant potential of GISTs, with high expression correlated with malignancy and poor prognosis.

Keywords: Gastrointestinal stromal tumors, CC chemokine receptor type 8, Malignant phenotype, Prognosis, STRING database, Immune regulation

Core tip: Although the application of c-kit inhibitors prolonged survival for advanced gastrointestinal stromal tumor (GIST) patients, the prognosis was not optimistic. Because of the role in tumor immunity, chemokine receptors have been identified as independent prognostic factors in various cancers but have not been investigated in GISTs. We evaluated CC chemokine receptor type 8 expression in GISTs by immunohistochemistry and analyzed its relationships with clinicopathological features and prognosis. We also investigated its role in tumor immunity. These confirmed that CC chemokine receptor type 8 can be used as an independent prognostic factor for GISTs and even as a potential therapeutic target.