Published online Aug 21, 2020. doi: 10.3748/wjg.v26.i31.4656
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 remains the main treatment for GISTs. Unfortunately, more than 50% of patients eventually develop local recurrence or metastasis. Although imatinib is the standard first-line therapy for patients with metastatic or advanced GISTs, it cannot cure the disease. The prognosis of the advanced cases is not optimistic. 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. However, there are only a few references on the expression of CCR8 protein in gastrointestinal stromal tumors.
The following problems, which we need to solve urgently, are also the research motivation of this article: (1) The function of the CCR8 in tumor immunity; (2) The relationship between the CCR8 expression and GIST clinical data; and (3) The relationship between the prognosis of GIST and CCR8.
In this study, we examined the expression of CCR8 in GISTs by immuno-histochemistry to explore the clinical significance of GIST expression and its prognosis. Based on the STRING database, we predicted the potential immunological function of CCR8. This research will provide evidence and support for the diagnosis of GIST, prognostic evaluation and new tumor treatment targets.
Tissue samples were used for the tissue microarray 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 im-munohistochemistry 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 field 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.
The expression of CCR8 protein in GISTs correlated with tumor size, mitotic index, AFIP-Miettinen risk classification. Each index suggested that the higher the degree of malignancy was associated with higher CCR8 expression. When compared with other factors (age, sex, tumor location, etc), there was no relationship with CCR8. CCR8 low expression was positively correlated with the survival of patients with GISTs, which has some implications for the prognosis of patients. CCR8 can be used as an independent factor to evaluate the prognosis of GISTs. 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. These will provide ideas for future research about the specific mechanism of CCR8 in tumor immunity.
Tumor immunity is currently a hotspot in cancer research, and the chemokine ligand/receptor axis plays an important role in the tumor immune mechanism of which CCR8 is the most brilliant one. Meanwhile, more and more studies focus on the immunopathogenesis of gastrointestinal stromal tumors. However, data on the relationship between CCR8 and the pathogenesis and treatment of GIST still remains unclear. This article is only a preliminary exploration of the study of CCR8 in gastrointestinal stromal tumors. The specific immunological mechanism of CCR8 in gastrointestinal stromal tumors is worthy of further exploration. We believe CCR8 could be a potential therapeutic target of GISTs.