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CCR8

Official Full Name
C-C motif chemokine receptor 8
Organism
Homo sapiens
GeneID
1237
Background
This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptors are important for the migration of various cell types into the inflammatory sites. This receptor protein preferentially expresses in the thymus. I-309, thymus activation-regulated cytokine (TARC) and macrophage inflammatory protein-1 beta (MIP-1 beta) have been identified as ligands of this receptor. Studies of this receptor and its ligands suggested its role in regulation of monocyte chemotaxis and thymic cell apoptosis. More specifically, this receptor may contribute to the proper positioning of activated T cells within the antigenic challenge sites and specialized areas of lymphoid tissues. This gene is located at the chemokine receptor gene cluster region. [provided by RefSeq, Jul 2008]
Synonyms
CY6; TER1; CCR-8; CKRL1; CDw198; CMKBR8; GPRCY6; CMKBRL2; CC-CKR-8;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVLVVCKKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSSMFFITLMSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGVLQCYSFYNQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLVLIVVIASLLFWVPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIYAFVGEKFKKHLSEIFQKSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL
Open
Disease
Psoriasis, Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
1 +

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Detailed Information

Characterized as a seven-transmembrane protein similar to G protein-coupled receptors, the CCR8 gene codes a member of the beta chemokine receptor family. Migration of different immune cell types to areas of inflammation depends on these receptors and their ligands. CCR8 is especially selectively expressed in the thymus, where it is essential for the control of immune responses. Studies pointing to CCR8's effect on monocyte chemotaxis and death in thymic cells have revealed the ligands for this receptor: notably I-309, Thymus Activation-Regulated Cytokine (TARC), and Macrophage Inflammatory Protein-1 beta (MIP-1 beta). The location of activated T cells in areas of antigenic challenge and specialized regions within lymphoid tissues also depends on this gene. Living in the chemokine receptor gene cluster emphasizes its importance for immune system operation.

Overview of CCR8 and Its Association with Cancer

Associated with many disorders, including Molluscum Contagiosum and Ileitis, CCR8 (C-C Motif Chemokine Receptor 8) is a protein-coding gene. With Gene Ontology annotations linked to G protein-coupled receptor activity and chemokine receptor activity, its functional pathways include Class A/1 (Rhodopsin-like receptors) and GPCR downstream signaling. CCR4 is a major paralog of this gene that emphasizes the link among chemokine signaling pathways.

Many immune checkpoints have been investigated clinically for use in cancer therapy after successful immunotherapies aiming at the PD-1/PD-L1 axis in solid tumors. Nevertheless, tumor-infiltrating regulatory T cells (Tregs) be essential for immunological tolerance and the creation of an immunosuppressive environment inside tumors, therefore compromising the effectiveness of these treatments. Clinical efforts to directly target or eradicate Tregs inside the tumor microenvironment have been attempted to meet this challenge; nonetheless, success has proved elusive.

High CCR8 expression has been linked, according to research, to numerous diseases including colorectal cancer, breast cancer, gastric cancer, metastatic brain cancer, and metastatic liver cancer. Especially high CCR8 levels have been found on Tregs extracted from breast cancer patients, therefore identifying CCR8 as a new and important immunological target in oncology.

Structural Characteristics and Ligands

Comprising 355 amino acids, CCR8 is a GPCR with a seven-times membrane-spanning structure. While in mice CCR8 has three known ligands: CCL1, CCL8, and CCL16, as part of the chemokine receptor subfamily CCR8 has four: CCL1, CCL8, CCL16, and CCL18 in humans. The main ligand for CCR8, CCL1 is the sole known receptor for this chemokine.

The development of different tumors depends critically on the interaction of CCR8 with its ligands, which also controls processes of tumor immune evasion. Shapes the tumor microenvironment and influences Treg recruitment, especially via the CCL1-CCR8 axis.

Mechanisms of Action of CCR8

The CCL1-CCR8 signaling pathway best illustrates the many functions of CCR8 in tumor development. CCL1 activates CCR8 receptors on cancer cells, therefore boosting proliferation, resistance to apoptosis, and increased migratory capacity, upon release into the tumor microenvironment by tumor stem cells, carcinoma-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs). Moreover, CCL1 affects endothelial cells which cause greater angiogenesis. Recruitment of Tregs to the tumor microenvironment and facilitation of the conversion of CD4+ T cells into Tregs—a process reliant on transforming growth factor-beta (TGF-β)—are fundamental aspects of CCL1's functioning. Supporting Treg activities within the tumor niche helps CCL1 maintain the immunosuppressive environment, so blocking the CCL1-CCR8 axis has great potential for malignant tumor treatment.

Figure 1 illustrates how CCL1 activates the CCR8 receptor in the cancer microenvironment, promoting tumor cell proliferation, apoptosis resistance, migration, and angiogenesis, while also recruiting regulatory T cells.Figure 1. The role of the CCL1→CCR8 axis in cancer.

The Role of CCR8+ Tregs in Immune Suppression

Fundamental to preserving immunological homeostasis and stifling too-strong immune responses are Tregs, a subgroup of CD4+ cells. Their especially important contribution to tumor immune evasion is their ability to prevent the activation and spread of effector T cells that could otherwise target tumor cells. CCL1 helps FOXP3+CCR8+ Tregs be recruited to tumor locations by not only bringing these immunosuppressive cells into the tumor but also by elevation of CCR8 expression on Tregs, hence improving their activity. By causing calcium flux and STAT3-dependent production of immunosuppressive markers like FOXP3, CD39, IL-10, and granzyme B, this upregulation increases the immune suppressive capacity of tumor-infiltrating Tregs.

Therapeutic approaches aiming at CCR8 may therefore either decrease tumor-infiltrating FOXP3+CCR8+ Tregs or interfere with the CCL1/CCR8 pathway, hence increasing anti-tumor immunity.

Research and Development of CCR8-Targeting Drugs

Several contenders are in the advanced phases of research. Among those driving the charge are LianBio's LM-108, Shionogi's S-531011, and Bristol-Myers Squibb's BMS-986340. Notable as the first monoclonal antibody aimed against CCR8 to get through clinical testing is BMS-986340. Using fucosylation reduction, its design improves antibody-dependent cellular cytotoxicity (ADCC). Bristol-Myers Squibb started a Phase I/II clinical study in May 2021 to evaluate the effectiveness of BMS-986340 in conjunction with other treatments for different solid tumors.

References:

  1. Korbecki J, Grochans S, Gutowska I, 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. Int J Mol Sci. 2020;21(20):7619. Published 2020 Oct 15.
  2. Moser B. Chemokine Receptor-Targeted Therapies: Special Case for CCR8. Cancers (Basel). 2022;14(3):511. Published 2022 Jan 20.
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