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Therapies for tumors continue to develop,and tumor immunotherapy has emerged as an effective means of controlling tumor progression.Given the limitations of immunotherapy,only some specific patients can benefit from immunotherapy.Since the complex tumor microenvironment is highly influenced by individual variability,immunotherapy will be subjected to different degrees of immune suppression in different tumor microenvironments and thus cannot exert its full effect.In the tumor microenvironment,regulatory T(Treg)cell plays as an immunosuppressive role.Numerous Treg cells infiltrate in indifferent tumor types,resulting in immune escape of tumor tissues,which will have a negative impact on treatment and prognosis.CC chemokine receptor 8(CCR8)belongs to the CC chemokine receptor family.CCR8 is specifically expressed on Treg cell in the tumor microenvironment and expressed at low level in the surrounding normal tissues and peripheral blood thus it can be a specific marker for Treg cell.CCR8 is a potential therapeutic target and biomarker.This review summarized the research progress of CCR8 in different tumor types in recent years,so as to provide reference for subsequent research.

RESUMEN

The human CC chemokine receptor 8 (CCR8) is a promising drug target for cancer immunotherapy and autoimmune disease. Besides human and viral chemokines, previous studies revealed diverse classes of CCR8-targeting small molecules. We characterized a selection of these CCR8 ligands (hCCL1, vCCL1, ZK756326, AZ6; CCR8 agonists and a naphthalene-sulfonamide-based CCR8 antagonist), in in vitro cell-based assays (hCCL1AF647 binding, calcium mobilization, cellular impedance, cell migration, ß-arrestin 1/2 recruitment), and used pharmacological tools to determine G protein-dependent and -independent signaling pathways elicited by these ligands. Our data reveal differences in CCR8-mediated signaling induced by chemokines versus small molecules, which was most pronounced in cell migration studies. Human CCL1 most efficiently induced cell migration whereby Gßγ signaling was indispensable. In contrast, Gßγ signaling did not contribute to cell migration induced by other CCR8 ligands (vCCL1, ZK756326, AZ6). Although all tested CCR8 agonists were full agonists for calcium mobilization, a significant contribution for Gßγ signaling herein was only apparent for human and viral CCL1. Despite both Gαi- and Gαq-signaling regulate intracellular Ca2+-release, cellular impedance experiments showed that CCR8 agonists predominantly induce Gαi-dependent signaling. Finally, small molecule agonists displayed higher efficacy in ß-arrestin 1 recruitment, which occurred independently of Gαi signaling. Also in this latter assay, only hCCL1-induced activity was dependent on Gßγ-signaling. Our study provides insight into CCR8 signaling and function and demonstrates differential CCR8 activation by different classes of ligands. This reflects the ability of CCR8 small molecules to evoke different subsets of the receptor's signaling repertoire, which categorizes them as biased agonists.

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Receptores CCR8/agonistas , Receptores CCR8/antagonistas & inhibidores , Transducción de Señal/fisiología , Quimiocina CCL1/administración & dosificación , Quimiocina CCL1/metabolismo , Quimiocina CCL8/administración & dosificación , Quimiocina CCL8/metabolismo , Quimiocinas CC/administración & dosificación , Quimiocinas CC/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Células Jurkat , Ligandos , Receptores CCR8/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

OBJECTIVE: To investigate the protein expression of CC chemokine ligand 1 (CCL1) and CC chemokine receptor 8 (CCR8) in the lung tissue of rats and the mechanism of acupuncture and moxibustion at "Feishu"(BL13), "Dazhui" (GV14) and "Fengmen"(BL12) in the treatment of asthma. METHODS: Sprague-Dawley rats were randomly divided into blank， model, acupuncture and moxibustion groups，n=10 in each group. Ovalbumin sensitization via intraperitoneal injection was performed to establish a model of asthma. The rats in the acupuncture group and the moxibustion group were given acupuncture for 20 min or circling moxibustion for 10 min at BL13, GV14 and BL12, once a day for 7 days. H.E. staining was used to observe the morphological changes of lung tissue. Real-time fluorescence quantitative PCR was used to measure the mRNA expression of signal transducer and activator of transcription 6 (STAT6) in lung tissue and immunohistochemistry was used to measure the protein expression of CCL1 and CCR8 in lung tissue. RESULTS: H.E. staining showed that the rats in the blank group had regular bronchial lumens and alveolar arrangement, with no inflammatory cell infiltration and aggregation around the bronchi; the rats in the model group had the infiltration and aggregation of a large number of inflammatory cells around the bronchi, stenosis of bronchial lumens, wall thickening, and alveolar structural disorder; compared with the model group, the acupuncture group and the moxibustion group had lower degrees of inflammatory cell infiltration and aggregation around the bronchi, stenosis of bronchial lumens, and wall thickening, as well as regular alveolar arrangement. The model group had significantly higher protein expression of CCL1 and CCR8 and mRNA expression of STAT6 than the blank group (P<0.05), and the acupuncture group and the moxibustion group had significantly lower protein expression of CCL1 and CCR8 and mRNA expression of STAT6 (P<0.05). CONCLUSION: Acupuncture and moxibustion can intervene against airway inflammation by inhibiting the protein expression of CCL1 and CCR8 and STAT6 signal transduction in lung tissue, which may be one of the mechanisms of acupuncture and moxibustion in the treatment of asthma.

Asunto(s)

Terapia por Acupuntura , Asma , Moxibustión , Animales , Quimiocina CCL1 , Ratas , Ratas Sprague-Dawley , Receptores CCR8

RESUMEN

OBJECTIVE: To investigate the protein expression of CC chemokine ligand 1 (CCL1) and CC chemokine receptor 8 (CCR8) in the lung tissue of rats and the mechanism of acupuncture and moxibustion at "Feishu"(BL13), "Dazhui" (GV14) and "Fengmen"(BL12) in the treatment of asthma. METHODS: Sprague-Dawley rats were randomly divided into blank， model, acupuncture and moxibustion groups，n=10 in each group. Ovalbumin sensitization via intraperitoneal injection was performed to establish a model of asthma. The rats in the acupuncture group and the moxibustion group were given acupuncture for 20 min or circling moxibustion for 10 min at BL13, GV14 and BL12, once a day for 7 days. H.E. staining was used to observe the morphological changes of lung tissue. Real-time fluorescence quantitative PCR was used to measure the mRNA expression of signal transducer and activator of transcription 6 (STAT6) in lung tissue and immunohistochemistry was used to measure the protein expression of CCL1 and CCR8 in lung tissue. RESULTS: H.E. staining showed that the rats in the blank group had regular bronchial lumens and alveolar arrangement, with no inflammatory cell infiltration and aggregation around the bronchi; the rats in the model group had the infiltration and aggregation of a large number of inflammatory cells around the bronchi, stenosis of bronchial lumens, wall thickening, and alveolar structural disorder; compared with the model group, the acupuncture group and the moxibustion group had lower degrees of inflammatory cell infiltration and aggregation around the bronchi, stenosis of bronchial lumens, and wall thickening, as well as regular alveolar arrangement. The model group had significantly higher protein expression of CCL1 and CCR8 and mRNA expression of STAT6 than the blank group (P<0.05), and the acupuncture group and the moxibustion group had significantly lower protein expression of CCL1 and CCR8 and mRNA expression of STAT6 (P<0.05). CONCLUSION: Acupuncture and moxibustion can intervene against airway inflammation by inhibiting the protein expression of CCL1 and CCR8 and STAT6 signal transduction in lung tissue, which may be one of the mechanisms of acupuncture and moxibustion in the treatment of asthma.