CCR4

Detailed Information

The CCR4 (C-C motif chemokine receptor 4) gene is located on human chromosome 3p22.1 and encodes a member of the class A (rhodopsin-like) G protein–coupled receptor (GPCR) superfamily. The gene contains three exons and two introns and encodes a seven-transmembrane protein of 360 amino acids with an approximate molecular weight of 41 kDa. Structurally, CCR4 exhibits the canonical features of GPCRs: an extracellular N-terminal domain responsible for ligand recognition and binding; seven transmembrane α-helices that form the ligand-binding pocket and mediate signal transduction; and an intracellular C-terminal domain involved in G protein coupling and receptor regulation. Within its extracellular loops, CCR4 harbors several conserved cysteine residues, which may form disulfide bonds to stabilize receptor conformation. The N-terminal region is rich in acidic amino acid residues, which are critical for the high-affinity binding of chemokine ligands. From an evolutionary perspective, CCR4 is highly conserved among mammals, underscoring its essential and irreplaceable role in immune system function.

Regulation of CCR4 Expression

CCR4 expression is controlled by complex transcriptional and post-transcriptional mechanisms. Its promoter region contains multiple transcription factor binding sites, including those for NF-κB, STAT, and GATA3, which play pivotal roles in T cell differentiation and activation. Epigenetic modifications, such as histone modifications and DNA methylation, also influence CCR4 transcriptional activity. At the protein level, receptor activity and expression are tightly regulated by processes including internalization, recycling, and degradation. Upon agonist binding, CCR4 undergoes β-arrestin–mediated internalization, with some receptors degraded and others recycled back to the plasma membrane. This dynamic balance ensures that cells maintain sensitivity and responsiveness to chemokine gradients. Dysregulated CCR4 expression or activity has been linked to various pathological conditions, including autoimmune diseases, allergic disorders, and malignancies, making CCR4 an attractive therapeutic target.

Biological Function and Immunological Significance

As a key member of the CC chemokine receptor family, CCR4 primarily mediates immune cell migration and activation. It displays high ligand selectivity for CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC). These chemokines, secreted by dendritic cells, macrophages, endothelial cells, and certain epithelial cells, generate gradients within lymphoid organs and tissue microenvironments to direct the migration of CCR4-expressing cells. Ligand binding to CCR4 induces conformational changes that activate Gi proteins, leading to phospholipase C-β (PLC-β) activation, inositol trisphosphate (IP3) and diacylglycerol (DAG) production, intracellular calcium mobilization, and protein kinase C activation. These downstream signaling events ultimately drive cytoskeletal reorganization and cell motility.

Figure 1. Schematic illustration of the molecular signaling pathways activated by CCR4. (Zengarini C, et al., 2024)

CCR4 expression is highly cell–type–specific within the immune system. It is predominantly expressed on distinct T cell subsets, including regulatory T cells (Tregs), T helper 2 (Th2) cells, and certain Th17 cells. This expression pattern positions CCR4 as a critical mediator of immune homeostasis and inflammation. For instance, Tregs are recruited via the CCR4–CCL22/CCL17 axis to sites of inflammation or tumor microenvironments, where they exert immunosuppressive functions that maintain self-tolerance and prevent excessive inflammation. However, in cancer, this recruitment mechanism can be exploited by tumor cells to suppress antitumor immune responses and promote immune evasion. Similarly, CCR4 expression on Th2 cells is central to their role in allergic responses and antiparasitic immunity, as these cells secrete IL-4, IL-5, and IL-13, which drive eosinophilic inflammation and IgE class switching.

Beyond adaptive immunity, CCR4 is also expressed on certain innate immune cells, including natural killer (NK) cells, dendritic cells, and platelets. In the central nervous system, CCR4 expression has been detected on microglia and subsets of neurons, suggesting roles in neuroimmune interactions and neuroinflammation. Evidence indicates that CCR4 signaling may promote hippocampal neuron survival through PI3K/Akt and ERK/MAPK pathways, implicating a neuroprotective function. Thus, the diverse cellular and tissue expression of CCR4 highlights its multifaceted biology, encompassing immune cell trafficking, tissue homeostasis, and repair. Elucidating the cell-type– and context-specific functions of CCR4 is crucial for the development of targeted therapeutic strategies.

Clinical Relevance and Therapeutic Applications

Aberrant expression and activation of CCR4 are implicated in numerous diseases, especially hematologic malignancies and autoimmune disorders. In adult T-cell leukemia/lymphoma (ATLL), malignant T cells typically overexpress CCR4, a feature associated with disease progression and poor prognosis. Mechanistic studies suggest that ATLL cells exploit CCR4-mediated migration to infiltrate skin and other tissues, producing characteristic clinical manifestations. Similarly, in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides and Sézary syndrome, CCR4 overexpression is a common feature, providing a rationale for targeted therapies. Beyond hematologic cancers, CCR4 expression also carries clinical significance in solid tumors. In breast cancer, gastric cancer, and head and neck squamous cell carcinoma, CCR4 expression on tumor cells or tumor-infiltrating lymphocytes correlates with disease progression and metastatic potential, often by recruiting Tregs to establish immunosuppressive microenvironments.

Therapeutic strategies targeting CCR4 have focused primarily on monoclonal antibodies and small-molecule inhibitors. Mogamulizumab (KW-0761), a defucosylated humanized anti-CCR4 monoclonal antibody, represents a breakthrough. It eliminates CCR4-positive cells via antibody-dependent cellular cytotoxicity (ADCC), and clinical studies have demonstrated significant efficacy in relapsed or refractory ATLL and CTCL. The pivotal MAVORIC trial confirmed that Mogamulizumab significantly prolonged progression-free survival compared with vorinostat in patients with mycosis fungoides and Sézary syndrome, leading to its approval in the United States, Japan, and Europe. Importantly, Mogamulizumab exerts dual mechanisms of action: direct targeting of malignant cells and depletion of immunosuppressive Tregs, thereby enhancing antitumor immunity.

In addition to antibody therapies, small-molecule CCR4 antagonists are under development. These compounds competitively block chemokine binding to CCR4, thereby inhibiting downstream signaling and cell migration. For example, FLX475, an orally bioavailable CCR4 antagonist, has been shown in preclinical studies to block Treg trafficking to tumors and enhance antitumor immunity. Early-phase clinical trials are evaluating FLX475 as monotherapy and in combination with PD-1 inhibitors for various solid tumors. Other innovative approaches include bispecific antibodies, antibody–drug conjugates (ADCs), and CAR-T cell therapies designed to enhance specificity and efficacy. Outside oncology, CCR4 antagonists are being developed for allergic diseases such as asthma and atopic dermatitis, as well as autoimmune diseases including rheumatoid arthritis and multiple sclerosis, owing to CCR4’s pivotal role in regulating Th2 and Treg cell trafficking.

Despite these promising advances, challenges remain. Resistance may arise through CCR4 downregulation or alterations in downstream signaling pathways, necessitating combination strategies. Immune-related adverse events, such as skin reactions and autoimmune phenomena observed during Mogamulizumab treatment, are of particular concern and may reflect Treg depletion. Future research should focus on identifying predictive biomarkers, optimizing dosing regimens, designing next-generation selective inhibitors, and exploring rational combination therapies. With deepening insights into CCR4 biology and advances in therapeutic technology, CCR4-targeted therapies hold great promise for improving clinical outcomes across a spectrum of diseases.

Reference

1. Zengarini C, Guglielmo A, et al. A Narrative Review of the State of the Art of CCR4-Based Therapies in Cutaneous T-Cell Lymphomas: Focus on Mogamulizumab and Future Treatments. Antibodies (Basel). 2024 Apr 22;13(2):32.

2. Beygi S, Duran GE, et al. Resistance to mogamulizumab is associated with loss of CCR4 in cutaneous T-cell lymphoma. Blood. 2022 Jun 30;139(26):3732-3736.