Unveiling the Role of CCR8 A Promising Tumor Immune Target

Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. The understanding of the cellular distribution and function of CCR8 in physiological and pathophysiological processes makes CCR8 a promising new target for cancer therapy that can be considered in future translational research.

CCR8 and CCR8 Ligands

CCR8 (Chemokine receptor 8) is a seven-transmembrane G protein-coupled receptor belonging to the chemokine receptor subfamily C-C. CCR8 is expressed on Th2 cells, monocytes and NK cells, and not on Th1 cells. In addition, CCR8 is also expressed on Treg cells, with high expression on tumor-infiltrating Treg cells and lower expression on Treg cells in the thymus, spleen, and peripheral blood. CCR8 is involved in the developmental process of a variety of tumors as well as mediating immunity to tumors through interactions with its ligands. The high specific expression of CCR8 on Treg at tumor sites suggests that CCR8 is a very good biomarker for Treg cells at tumor sites, and is a very promising target for tumor immunity. There are four known ligands for human CCR8: CCL1, CCL8, CCL16, and CCL18. CCR8 is the only known receptor for CCL1.

Significance of CCL1-CCR8 in Cancer

Human CCL1 is the primary ligand for human CCR8 and binds to both CCR8 extracellular loop 2 (ECL2) and the N-terminal structural domain of CCR8. In the tumor microenvironment, CCL1 secreted by tumor stem cells, CAF (carcinoma-associated fibroblasts) and TAM (tumor-associated macrophages), exerts its function by acting on CCR8 receptors on different cell surfaces:

CCL1 activates CCR8 receptors on cancer cells, leading to proliferation, apoptosis resistance and migration.
In addition to its effects on cancer cells, CCL1 causes angiogenesis by activating CCR8 receptors on endothelial cells.
Another important function of CCL1 is the recruitment of Treg to the tumor ecological niche and its involvement in the conversion of CD4+ T cells to Treg.

Fig. 1 The significance of the CCL1→CCR8 axis in cancer processes. (Korbecki, J. et al., 2020)

The process of CD4+ T cell to Treg transformation is dependent on transforming growth factor-β (TGF-β). CCL1 supports the immunosuppressive function of Treg in the tumor ecosystem. Blocking the CCL1-CCR8 axis serves as a novel immune checkpoint-based therapeutic approach for malignant tumors.

Significance of CCL18-CCR8 in Cancer

In tumors, CCL18 is produced and secreted by TAM, which acts in an autocrine manner on these cells. It also causes cancer cell migration and invasion through the receptors PITPNM3 and CCR8.CCL18 plays an important role in angiogenesis by acting on PITPNM3 on endothelial cells. It also leads to the entry of nave CD4+ T cells into the tumor ecological niche and the conversion of CD4+ T cells to Treg cells.

CCR8 and Treg cell-mediated immunosuppression CCR8+ regulatory T cells (Treg cells) are drivers of immunosuppression. CCR8 is an immunosuppressive receptor that mediates immune escape of tumor cells.CCR8-mediated immunosuppression of Treg cells is broadly described below:

CCL1 is able to recruit FOXp3+CCR8+ Treg cells to infiltrate into tumor tissues and exercise immunosuppressive functions through interaction with its ligand CCR8, while it can induce up-regulation of CCR8 expression on the surface of FOXp3+ Treg cells, induce Ca2+ flow, and induces stat3-dependent up-regulation of Foxp3, CD39, IL-10, and granzyme B expression, which in turn enhances the immunosuppressive activity of these tumor-infiltrating Treg cells. CCR8 was highly expressed on FOXP3+ Tregs in patients' tumor tissues and significantly reduced in patients' blood. This is in contrast to targets such as CCR4, CTLA-4, and CD25, which have little difference in expression on tumor and blood Tregs. The specific expression of CCR8 on Treg cells at the tumor site makes it promising that the development of CCR8-targeted monoclonal antibody drugs could then specifically inhibit the function of Tregs at the tumor site, contributing to cancer therapy.

Fig. 2 The significance of CCL18 in cancer processes. (Korbecki, J. et al., 2020)

Drug Studies Against CCR8 Targets

CCR8 represents a promising target for cancer immunotherapy. Guided by mogamulizumab, an ADCC-activated antibody against CCR8 binds to and eliminates tumor-associated Treg cells, in particular the most activating and inhibitory fractions of Treg cells that selectively express this chemokine receptor.

Below is information about the drugs and mechanisms of action related to CCR8 targets:

Target	Name	Description	Mode of Action
CCR8	AZ084	CCR8 allosteric antagonist	Blocks LT, DC and eosinophils migration
	JTX-1811	Humanized mAb (hIgG1)	CCR8+ Tregs depletion by ADCC
	SRF114	Humanized mAb (hIgG1)	CCR8+ Tregs depletion by ADCC Blocks CCR8+ Tregs migration
	HBM1022	Humanized mAb (hIgG1)	CCR8+ Tregs depletion by ADCC Blocks CCR8+ Tregs migration
	FPA157	Humanized mAb (hIgG1)	CCR8+ Tregs depletion by ADCC Blocks CCR8+ Tregs migration
	25B3	Humanized mAb (non fucosylated hIgG1)	CCR8+ Tregs depletion by ADCC

CCR8 Related Products & Applications

At Creative Biogene, we offer a range of high-quality, ready-to-use products designed to facilitate research and exploration of the CCR8 pathway. With a focus on transfected stable cell lines, preformed viral particles, and virus-like particles (VLPs), we provide researchers with a powerful resource to study CCR8 function and its relevance to drug discovery.

Transfected stable cell lines

Our stable cell lines are engineered to express CCR8 or its variants, providing a reliable and consistent model for studying CCR8-related functions, signaling pathways, and drug responses. These cell lines can serve as valuable tools to investigate the role of CCR8 in immune responses, inflammation, cancer progression, and more.

Cat.No.	Product Name	Price
CSC-DC002678	Panoply™ Human CCR8 Knockdown Stable Cell Line	Inquiry
CSC-SC002678	Panoply™ Human CCR8 Over-expressing Stable Cell Line	Inquiry
CSC-RG1143	Human CCR8 Stable Cell Line-CHO	Inquiry
CSC-RG1808	Human CCR8 Stable Cell Line - CT26	Inquiry
CSC-RG1810	Human CCR8 Stable Cell Line - HEK293T	Inquiry
CSC-RG1829	Human CCR8 Stable Cell Line-HEK293	Inquiry
CSC-RG1804	Mouse Ccr8 Stable Cell Line - HEK293T	Inquiry
CSC-RG1805	Mouse Ccr8 Stable Cell Line - CHO-K1	Inquiry
CSC-RG1796	Rat Ccr8 Stable Cell Line - HEK293T	Inquiry
CSC-RG1802	Monkey CCR8 Stable Cell Line - CHO-K1	Inquiry
CSC-RG1811	Monkey CCR8 Stable Cell Line - HEK293T	Inquiry

Preformed viral particles

Our preformed viral particles, such as lentiviral or adenoviral particles, carry CCR8 genes or shRNA constructs designed to modulate CCR8 expression. These particles offer an efficient and targeted approach to deliver CCR8-related genetic material into specific cell types. Researchers can utilize these particles for functional studies, gene knockdown experiments, or to investigate the impact of altered CCR8 expression on cellular behavior.

Cat.No.	Product Name	Price
AD03286Z	Human CCR8 adenoviral particles	Inquiry
LV08314L	Human CCR8 (NM_005201) lentivirus particles	Inquiry

Virus-like particles (VLPs)

Cat.No.	Product Name	Price
VLP-N-00022	Human CCR8 Virus-Like Particles	Inquiry

References:

Korbecki, J.; et al. CC chemokines in a tumor: a review of pro-cancer and anti-cancer properties of receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands. International journal of molecular sciences. 2020, 21(20): 7619.
Moser, B. Chemokine receptor-targeted therapies: special case for CCR8. Cancers. 2022, 14(3): 511.

* For research use only. Not intended for any clinical use.

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