Background and objective:High morbidity, high mortality and poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the urgent need for novel therapeutic strategies against ESCC. The current study addresses the precise role of M2-like macrophages-derived CCL17 in ESCC progression and to thoroughly elucidate the intrinsic molecular mechanisms.Methods:In this work, for functional experiments, Eca109 cells cultivated in M2-CM were treated with anti-IgG (50 μg/ml) or anti-CCL17 (50 μg/ml) to expound the tumorpromoting effects of M2-like macrophage-derived CCL17 in ESCC. Moreover, for rescue experiments, Eca109 cells were treated with CCL17 (50 ng/ml) and/or CCR4 antagonist AZD2098 (20 μM) to probe whether CCL17 could influence the malignant behaviors including migration, invasion and stemness of ESCC cells via activating CCR4/ERK/PD-L1 pathway.Results:Markedly enhanced CCL17 secretion was observed in M2-like macrophages. CCL17 bound to CCR4 to activate ERK/PD-L1 signaling. M2-like macrophagesderived CCL17 facilitated ESCC cell migration and invasion and enhanced stemness characteristics of ESCC cells, which were partially reserved by AZD2098 treatment. The tumor-promoting effects of M2-like macrophages-derived CCL17 on ECSS was depended on the activation of CCR4/ERK/PD-L1 pathway.Conclusion:To conclude, M2-like macrophages-derived CCL17 could facilitate ESCC cell migration and invasion and enhance stemness characteristics of ESCC cells via activating CCR4/ERK/PD-L1 signaling.

01 Oct 2024·Cancer Research Communications

Small-Molecule CCR4 Antagonists in Cutaneous T-cell Lymphoma

Article

Author: Ni, Xiao ; Han, Wei ; Wang, Xiaohong ; Bijani, Pedram ; Velatooru, Loka Reddy ; Enriquez, José S.

AbstractMycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor-4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. Although small-molecule CCR4 antagonists have been studied in other diseases involving CCR4+ Th2 cells and regulatory T cells, their effects in CTCL have not been previously explored. This study assessed the effects of two small-molecule CCR4 antagonists: C021 (class-I) and AZD-2098 (class-II) in MF-derived cell line (MJ) and SS-derived cell line (HuT 78) in vitro and in vivo. As per results, both C021 and AZD-2098 inhibited chemotactic responses to CCL17 and CCL22 in MJ and HuT 78 cells. However, only C021 downregulated CCR4 expression, inhibited cell proliferation, induced cell apoptosis and cell-cycle arrest, and decreased colony formation in MJ and HuT 78 cells in vitro. Furthermore, only C021 inhibited tumor growth in CTCL xenograft mice in vivo. These findings suggest that class-I CCR4 antagonists such as C021 exert more potent antitumor effects on CTCL cells in vitro and in vivo than do class-II CCR4 antagonists like AZD-2098, highlighting their potential for clinical application.Significance:Our findings are of interest to readers because they bring new evidence that small-molecule CCR4 antagonists may be an alternative therapeutic strategy to target CCR4+ CTCL cells. They may inhibit CCR4 function but not eradicate cells, so the side effects may be avoided or minimized.

01 Feb 2023·Stroke and Vascular Neurology

CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats

Article

Author: Liu, Yibo ; Yuan, Ling ; Wang, Xiaoyu ; Chen, Sheng ; Zhang, Anke ; Fang, Yuanjian ; Lenahan, Cameron ; Jiang, Junkun ; Xu, Houshi ; Zhang, Chuan ; Zhang, Jianmin ; Zhang, Zeyu ; Fang, Chaoyou

Background and purposeC-C motif chemokine ligand 17 (CCL17) presents an important role in immune regulation, which is critical in the pathophysiology of brain injury after subarachnoid haemorrhage (SAH). There is rare evidence to illustrate the function of CCL17 towards SAH. In this study, we try to reveal the therapeutic effects of CCL17 and its underlying mechanism in rat SAH model.MethodsSAH rat models were assigned to receive recombinant CCL17 (rCCL17) or phosphate buffer saline (PBS). AZD2098 and JR-AB2-011 were applied to investigate the C-C motif chemokine receptor 4 (CCR4)/mammalian target of rapamycin complex 2 (mTORC2) axis in CCL17-mediated neuroprotection. To elucidate the underlying mechanism, the in vitro kinase assay was performed in primary microglia. Microglial-specific Rictor knockdown was administered via intracerebroventricular injection of adenovirus-associated virus. Brain water content, short-term neurobehavioural evaluation, western blot analysis, quantitative RT-PCR and histological staining were performed.ResultsThe expression of CCL17 was increased and secreted from neurons after oxyhaemoglobin stimulation. Exogenous rCCL17 significantly alleviated neuronal apoptosis, and alleviated short-term neurofunction after SAH in rats. In addition, rCCL17 increased M2-like polarisation of microglia in rats post-SAH and in primary microglia culture. The neuroprotection of rCCL17 was abolished via inhibition of either CCR4 or mTORC2.ConclusionCCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.

100 Deals associated with AZD-2098

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Discovery	GB	AstraZeneca PLC	-
Kidney Neoplasms	Discovery	GB	Cancer Research UK	-

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