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CCR4

C-C chemokine receptor type 4 (CCR4), also known as CD194, is a seven-transmembrane G protein-coupled receptor encoded by the CCR4 gene on chromosome 3p22 in humans, primarily expressed on T helper type 2 (Th2) cells, regulatory T cells (Tregs), and skin-homing lymphocytes, where it binds the chemokines CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC) to facilitate immune cell chemotaxis and migration to inflammatory sites such as the skin and lungs.^[1]^[2] As a member of the CC chemokine receptor family, CCR4 plays a critical role in orchestrating adaptive immune responses by promoting the recruitment of Th2 cells and Tregs, which are essential for type 2 immunity, allergic inflammation, and immune tolerance.^[1]^[2] Physiologically, it mediates the homing of leukocytes to mucosal and cutaneous tissues, contributing to host defense against pathogens and maintenance of tissue homeostasis, while its activation triggers intracellular signaling via Gi/Go proteins, leading to calcium mobilization and directed cell movement.^[1]^[2] In pathology, CCR4 is implicated in various immune-mediated disorders, including asthma, atopic dermatitis, and autoimmune conditions, where its overexpression on Th2 cells exacerbates allergic responses and chronic inflammation.^[1]^[3] Notably, CCR4 is highly expressed in certain hematologic malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphomas (CTCLs), where it drives tumor cell trafficking to the skin and enables immune evasion by recruiting suppressive Tregs to the tumor microenvironment.^[2]^[4] Therapeutically, CCR4 has emerged as a promising target for immunotherapy, with the defucosylated monoclonal antibody mogamulizumab (approved by the FDA for relapsed or refractory CTCL; approved in Japan for relapsed or refractory ATLL) enhancing antibody-dependent cellular cytotoxicity to deplete CCR4-positive malignant and regulatory T cells, demonstrating improved progression-free survival in clinical trials.^[2] Ongoing research explores CCR4 antagonists and small-molecule inhibitors for broader applications in cancer, autoimmune diseases, and neuropathic pain, underscoring its dual role in immunity and disease.^[3]^[2]

Discovery and Nomenclature

Discovery

The CC chemokine receptor 4 (CCR4) was first identified through molecular cloning efforts in the mid-1990s, amid growing interest in the chemokine receptor family following the discovery of HIV coreceptors. In 1995, researchers cloned a novel cDNA encoding CCR4 from a human basophilic cell line (KU-812), using degenerate PCR primers based on conserved motifs in known G protein-coupled receptors.^[5] The full-length sequence revealed a 360-amino acid protein with seven transmembrane domains, characteristic of the CC chemokine receptor subfamily, and initial functional expression in Xenopus oocytes demonstrated calcium mobilization in response to certain CC chemokines like MIP-1α, though later studies refined its ligand specificity.^[5] Subsequent characterization in 1996-1997 confirmed CCR4's role as a receptor for specific Th2-associated chemokines. Early binding and chemotaxis assays identified CCL17 (thymus and activation-regulated chemokine, TARC) as a high-affinity ligand, with functional responsiveness demonstrated in transfected cells and primary T lymphocytes, highlighting CCR4's selective expression on T helper type 2 (Th2) cells.^[6] Shortly thereafter, CCL22 (macrophage-derived chemokine, MDC) was established as a second potent agonist, eliciting similar calcium fluxes and migration in CCR4-expressing cells, further solidifying its classification within the CC chemokine receptor family.^[7] CCR4 exhibits strong evolutionary conservation across mammals, reflecting its fundamental role in immune cell trafficking. The murine ortholog was cloned in 1996 from a genomic library, sharing 85% amino acid identity with the human protein and demonstrating comparable high-affinity binding to CC chemokines, enabling rapid cross-species functional studies.^[8] Orthologs in other mammals have also been identified, underscoring conserved structural features and ligand interactions essential for adaptive immunity.

Nomenclature

The official HGNC symbol for the gene encoding CCR4 is CCR4, with the approved full name C-C motif chemokine receptor 4.^[9] In humans, the CCR4 gene is assigned Entrez Gene ID 1233 and is located on chromosome 3p22.3.^[10] Common aliases for CCR4 include CKR4, K5.5, CC-CKR-4, and CMKBR4.^[11] CCR4 is classified as a member of the CC chemokine receptor subfamily, which consists of G protein-coupled receptors named CCR1 through CCR10 that specifically bind chemokines featuring a C-C motif (two adjacent cysteines) near the N-terminus of the ligand.^[12] The nomenclature for CCR4 and related chemokine receptors is standardized by the IUPHAR/BPS Guide to Pharmacology, with revisions in the 2020s—such as the 2020.5 and subsequent annual updates—aimed at ensuring consistency in the classification and annotation of these pharmacological targets across the G protein-coupled receptor superfamily.^[13]

Gene and Protein Structure

Gene Structure

The CCR4 gene is located on chromosome 3p22.3 in humans, spanning approximately 4.7 kb from position 32,951,644 to 32,956,349 on the forward strand (GRCh38 assembly).^[10] The gene consists of two exons separated by a single intron, with the coding sequence primarily distributed across these exons to encode the full-length protein product.^[10] The promoter region of CCR4 contains binding sites for key transcription factors involved in immune regulation, including NF-κB, which directly binds to the promoter and mediates TNF-α-induced expression of the gene.^[14] Additionally, the IL-4/STAT6 signaling pathway upregulates CCR4 transcription, with STAT6 playing a central role in this process as part of Th2 immune responses.^[15] Alternative splicing of the CCR4 pre-mRNA produces at least two transcript variants in humans, including the canonical full-length isoform (NM_005508.5) that is predominant and widely expressed, and a predicted shorter variant (XM_017005687.2).^[10] The full-length transcript encodes the functional receptor, while variant isoforms may arise from differential splicing at the 3' end, though their functional implications remain under investigation. Common single nucleotide polymorphisms (SNPs) in the CCR4 gene, such as the C1014T (rs2228428) variant in exon 2, are associated with alterations in mRNA stability and potential expression levels, with the T allele occurring at a frequency of approximately 12-20% in diverse populations.^[16] The genomic organization of CCR4, including its exon-intron boundaries, exhibits high conservation across primate species, reflecting evolutionary stability in the chemokine receptor family essential for immune function.

Protein Structure

The human CCR4 protein consists of 360 amino acids with a calculated molecular weight of approximately 41 kDa. It belongs to the class A subfamily of G-protein-coupled receptors (GPCRs) and exhibits the canonical topology of this superfamily, including an extracellular N-terminal domain involved in ligand recognition, seven transmembrane-spanning α-helices that form the core helical bundle, three extracellular loops (ECL1–3), three intracellular loops (ICL1–3) that facilitate G-protein interactions, and an intracellular C-terminal tail responsible for regulatory functions.^[17]^[11] Key structural motifs conserved among chemokine receptors include the DRY box (Asp-Arg-Tyr) motif located at the cytoplasmic end of transmembrane helix 3 (TM3), which is critical for G-protein coupling and receptor activation by stabilizing the inactive state and enabling conformational shifts upon activation. Additionally, a conserved disulfide bond between cysteine residues in ECL2 (Cys184) and the extracellular end of TM3 (Cys109) maintains the structural integrity of the extracellular region and supports proper ligand binding.^[17]^[18] Although no experimental atomic-resolution structure of CCR4 has been determined to date, homology models derived from cryo-EM structures of closely related chemokine receptors, such as CCR5 and CXCR4 obtained in the early 2020s, illustrate its molecular architecture. These models depict CCR4 as adopting an inactive conformation with a compact helical bundle in the absence of ligand, featuring a ligand-binding pocket formed by the N-terminus, ECL2, and TM helices 2, 3, 5, 6, and 7. Upon binding CCL17, the models predict ligand-induced conformational changes, including an outward tilt of TM6 by approximately 14 Å and rearrangements in the DRY box to facilitate G-protein engagement, consistent with activation mechanisms observed in other CC chemokine receptors.^[19]^[20] Post-translational modifications play essential roles in CCR4 maturation and regulation. The N-terminal extracellular domain contains three predicted N-glycosylation sites (at Asn5, Asn11, and Asn18), which contribute to protein folding, stability, and cell surface expression by shielding hydrophobic regions and preventing aggregation during biosynthesis. The intracellular C-terminal tail harbors multiple serine and threonine phosphorylation sites (e.g., Ser338, Ser342, Thr349), primarily targeted by G-protein-coupled receptor kinases (GRKs) following ligand stimulation, leading to β-arrestin recruitment, receptor desensitization, and endocytosis.^[21]^[17] CCR4 exhibits approximately 35% amino acid sequence identity with CCR5, another CC chemokine receptor, particularly in the transmembrane helical bundle, underscoring shared evolutionary origins and structural features such as the arrangement of the seven TM helices and conserved ligand-binding residues within the orthosteric pocket. This homology enables predictive modeling of CCR4 function based on CCR5 structures while highlighting unique residues in CCR4's extracellular domains that confer specificity for its ligands.^[19]

Ligands and Signaling

Natural Ligands

The primary natural ligands for the chemokine receptor CCR4 are the CC chemokines CCL17 (also known as thymus and activation-regulated chemokine or TARC) and CCL22 (also known as macrophage-derived chemokine or MDC). Both are selective agonists that bind to the orthosteric site on CCR4, inducing receptor activation and downstream signaling in immune cells such as T helper 2 (Th2) lymphocytes and regulatory T cells. CCL17 and CCL22 are primarily produced by antigen-presenting cells, including dendritic cells and monocytes/macrophages, as well as by Th2 cells under certain conditions, facilitating targeted recruitment in immune responses.^[6]^[7]^[22] Binding studies have demonstrated high-affinity interactions between these ligands and CCR4. For CCL17, the dissociation constant (KD) is approximately 0.5 nM, as measured by binding of TARC-secreted alkaline phosphatase fusion protein to CCR4-transfected cells. CCL22 exhibits even higher affinity, with a KD of 0.18 nM, determined through similar assays using MDC-secreted alkaline phosphatase on CCR4-expressing cells; competition experiments confirmed mutual displacement of the two ligands without interference from other CC chemokines like MCP-1 (CCL2). These affinities underscore the potency of both ligands, though CCL22 more effectively induces CCR4 internalization and desensitization compared to CCL17. N-terminal processing of these chemokines can modulate their activity: truncation of CCL22, often observed in supernatants from stimulated dendritic cells, abolishes its ability to bind CCR4 and elicit T-cell chemotaxis while preserving monocyte attraction via alternative receptors, thereby serving as a regulatory mechanism to fine-tune inflammatory responses. Similar processing of CCL17 reduces its potency, though to a lesser extent.^[6]^[7]^[23] In addition to the primary ligands, CCR4 exhibits weak interactions with other CC chemokines such as CCL2 (MCP-1) and CCL5 (RANTES), but these do not trigger functional signaling, including chemotaxis or calcium mobilization, even in highly sensitive assays. The expression of CCL17 and CCL22 is upregulated in inflammatory contexts by Th2-associated cytokines, particularly interleukin-4 (IL-4) and interleukin-13 (IL-13), which enhance production in fibroblasts, epithelial cells, and macrophages to amplify Th2-biased immune environments. Natural regulation of CCR4 activity also involves decoy receptors like D6 (ACKR2), which promiscuously binds CCL17 and CCL22 without signaling, scavenging these ligands to prevent excessive CCR4 activation in tissues.^[2]91321-7/fulltext)^[24]

Signaling Pathways

Upon ligand binding, CCR4, a G protein-coupled receptor (GPCR), primarily couples to heterotrimeric G proteins of the Gi/o family, leading to the dissociation of the Gαi/o subunit and the release of Gβγ subunits.^[25] This coupling inhibits adenylyl cyclase activity, resulting in decreased intracellular cyclic AMP (cAMP) levels, which modulates various cellular responses including chemotaxis.^[26] The downstream signaling cascades activated by CCR4 are mediated primarily through the Gβγ subunits, which recruit and activate effector proteins. Key pathways include the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, promoting cell survival and migration by phosphorylating Akt and downstream targets like FOXO transcription factors.^[27] Additionally, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is engaged, facilitating cell proliferation and gene expression changes via ERK1/2 phosphorylation.^[14] Parallel activation of phospholipase C β (PLCβ) hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), triggering IP3-mediated calcium mobilization from intracellular stores and DAG-dependent protein kinase C (PKC) activation.^[28] Recent studies have highlighted biased agonism at CCR4, where the ligands CCL17 and CCL22 elicit differential signaling profiles. CCL22 preferentially recruits β-arrestin over G protein pathways, enhancing ERK activation and desensitization, whereas CCL17 shows weaker β-arrestin engagement and more balanced G protein signaling, as demonstrated in T cell models during the 2020s.^[29]^[30] Desensitization of CCR4 occurs through agonist-induced phosphorylation by G protein-coupled receptor kinases (GRKs), primarily GRK2 and GRK3, on serine and threonine residues in the C-terminal tail and intracellular loops. This phosphorylation facilitates β-arrestin binding, which uncouples the receptor from G proteins, terminates signaling, and promotes clathrin-coated pit-mediated endocytosis for internalization and trafficking to lysosomes or recycling endosomes.^[31]^[32] CCR4 exhibits cross-talk with other chemokine receptors, such as CCR7, in T cell signaling, where co-expression modulates migratory responses; for instance, CCR4 activation can enhance CCR7-mediated chemotaxis in thymocytes by altering cytoskeletal dynamics and adhesion molecule expression.^[33]^[34]

Expression and Physiological Function

Cellular and Tissue Expression

CCR4 is predominantly expressed on specific immune cell types, including Th2-polarized CD4+ T lymphocytes, regulatory T cells (Tregs), cutaneous lymphocyte antigen-positive (CLA+) skin-homing T cells, and basophils.^[3]^[35]^[36] This selective cellular distribution underscores its role in directing Th2-biased and suppressive immune subsets to relevant sites. In terms of tissue distribution, CCR4 exhibits abundant expression in lymphoid and mucosal tissues such as the skin, lung, thymus, and spleen, based on integrated GTEx and Human Protein Atlas transcriptomics data up to 2025, with median normalized TPM values elevated in these sites relative to the overall median (e.g., ~4-16-fold in spleen, lung, and blood-derived tissues).^[11]^[37] In contrast, expression remains low in non-lymphoid organs like the brain and liver, where nTPM levels are near background.^[37] During development, CCR4 expression is upregulated in the thymus shortly after positive selection of thymocytes, facilitating their migration into the medulla for further maturation.^[33] In adult immune responses, CCR4 levels are dynamic, increasing on activated T cells to support recruitment during ongoing inflammation.^[23] CCR4 expression is induced upon T cell activation, particularly in CD4+ subsets, and can be modulated by cytokines in the microenvironment.^[23] Glucocorticoids contribute to its downregulation in maturing thymocytes and activated cells, aligning with broader immunosuppressive effects.^[33] Expression patterns of CCR4 are conserved across species, with similar profiles observed in mice, where Ccr4 knockout models display normal thymic development and viability despite the absence of the receptor.^[38]

Roles in Immune Response

CCR4 serves as a key mediator of immune cell migration in normal physiological responses, primarily through its interaction with the chemokines CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC). These ligands form gradients that direct the chemotaxis of CCR4-expressing cells, such as T helper 2 (Th2) cells and regulatory T cells (Tregs), toward sites of inflammation in the skin and mucosal tissues. This process is crucial for orchestrating targeted immune surveillance and response initiation without systemic disruption.^[2]^[39] In Th2-dominated immune processes, CCR4 facilitates the polarization and effector functions of Th2 cells by enabling their recruitment to environments rich in type 2 cytokines. The CCL17/CCR4 signaling axis enhances IL-4 and IL-13 production via pathways like ERK/STAT3, amplifying Th2 responses and supporting antibody class switching to IgE. Furthermore, CCR4 contributes to eosinophil recruitment, as these cells express the receptor and migrate in response to CCL17 and CCL22, thereby reinforcing type 2 inflammation and tissue repair mechanisms.^[40]^[41]^[42] CCR4 also plays an essential role in immune tolerance through Tregs, which predominantly express the receptor to home to lymphoid organs and peripheral tissues. This migration allows Tregs to exert suppressive effects on autoreactive or excessive effector T cells, maintaining homeostasis and preventing unwarranted inflammation. Unlike CCR5, which serves as a primary coreceptor for HIV entry, CCR4 has a limited direct role in viral tropism but supports CD4+ T cell positioning during broader antiviral immune responses by guiding their trafficking to infected sites.^[43]^[44]^[2] Studies in CCR4 knockout mice demonstrate viable animals with no overt lethality, underscoring the receptor's non-essential but modulatory nature in baseline immunity. These mice exhibit reduced Th2 cytokine production and impaired homing of Th2 cells and Tregs to the skin, leading to altered responses in cutaneous immune challenges while preserving overall development and survival.^[45]^[46]^[47]

Role in Pathophysiology

Involvement in Cancer

CCR4-expressing regulatory T cells (Tregs) accumulate in the tumor microenvironment of various malignancies, where they suppress antitumor immunity and promote disease progression. In breast cancer, tumor cells secrete CCL22, which recruits CCR4+ Tregs that inhibit effector T cell responses and correlate with adverse outcomes.^[48] Similarly, in colorectal cancer, increased infiltration of CCR4+ Tregs contributes to immune evasion by limiting cytotoxic activity against tumor cells.^[49] In Hodgkin's lymphoma, CCR4+ Tregs are highly enriched in lymphoid infiltrates, further dampening host immune surveillance and associating with tumor tolerance.^[2] The CCR4 pathway facilitates metastasis by fostering a Th2-skewed tumor microenvironment that supports angiogenesis and tumor spread. CCL22 secretion by tumor-associated macrophages attracts CCR4+ Th2 cells and Tregs, leading to elevated IL-4 production, which upregulates vascular endothelial growth factor (VEGF) and enhances blood vessel formation.^[50] In experimental breast cancer models, CCR4 signaling drives lung metastasis through sustained recruitment of immunosuppressive cells that remodel the extracellular matrix.^[51] This axis also promotes peritoneal dissemination in gastric cancer by enabling malignant cell survival in omental niches.^[52] High CCR4 expression serves as a prognostic marker in specific hematologic malignancies, particularly adult T-cell leukemia/lymphoma (ATLL), where it correlates with skin involvement and reduced overall survival.^[53] Approximately 90% of ATLL cases exhibit CCR4 on neoplastic cells, often with mutations that enhance receptor function and worsen prognosis.^[54] CCR4 overexpression is prominent in cutaneous T-cell lymphomas, including mycosis fungoides and Sézary syndrome, where elevated levels on malignant T cells predict poorer survival and drive lymphomagenesis.^[55] In solid tumors such as melanoma, CCR4 mediates skin homing of Tregs via CCL22 gradients, enabling their infiltration into dermal lesions and bolstering tumor immune escape.^[56] Insights from single-cell RNA sequencing in the 2020s have elucidated heterogeneity in CCR4 expression among tumor-infiltrating lymphocytes, revealing distinct Treg subsets with varying immunosuppressive potentials across cancer types like colorectal and lung tumors.^[57] These studies highlight functional diversity, such as CCR4+ Tregs co-expressing exhaustion markers, which adapt to the tumor niche and resist therapies.^[58]

Involvement in Autoimmune and Inflammatory Diseases

CCR4 plays a critical role in mediating the recruitment of T helper 2 (Th2) cells to inflamed tissues in allergic diseases such as atopic dermatitis (AD) and asthma, where its ligands CCL17 and CCL22 promote the migration of CCR4-expressing Th2 lymphocytes to the skin and airways, exacerbating type 2 inflammation.^[59] In AD, elevated levels of CCR4+ memory CD4+ T cells are observed in peripheral blood and lesional skin, contributing to chronic skin inflammation driven by Th2 cytokines like IL-4 and IL-13.^[60] Similarly, in asthma, CCR4 facilitates the infiltration of Th2 cells into the airway mucosa, as evidenced by increased CCR4 expression on airway T cells in atopic asthmatics, leading to eosinophilia, goblet cell hyperplasia, and airway hyperresponsiveness.^[61] In autoimmune diseases, CCR4 contributes to pathological immune responses by enabling the migration of proinflammatory T cell subsets across barriers. In rheumatoid arthritis (RA), CCR4 expression is upregulated on circulating CD4+ T cells and in synovial fluid, where it supports Th17 cell recruitment and expansion, promoting joint inflammation and destruction.^[62] CCR4+ T cells in RA synovium exhibit a Th2-like phenotype with increased IL-4 production, further amplifying autoimmune synovitis.^[63] In multiple sclerosis (MS), CCR4 aids the crossing of Th17 and other effector T cells through the blood-brain barrier, as demonstrated in experimental autoimmune encephalomyelitis (EAE) models where CCR4 antagonism reduces disease severity by limiting inflammatory macrophage infiltration into the central nervous system.^[64] CCR4 is also implicated in other chronic inflammatory conditions. In inflammatory bowel disease (IBD), particularly colitis, CCL22 produced by intestinal epithelial cells attracts CCR4+ regulatory T cells (Tregs), but dysregulated signaling leads to impaired Treg function and exacerbated mucosal inflammation in models of T cell transfer colitis.^[65] In systemic sclerosis (SSc), CCR4 expression on Th2 cells correlates with fibrotic progression, as CCR4+ T cells infiltrate skin and promote cytokine-driven fibrosis in bleomycin-induced models mimicking SSc pathology.^[66] As of 2025, CCR4 has been identified as a key modulator in early atherosclerotic plaque formation, where its deficiency exacerbates inflammatory responses, contributing to cardiovascular disease pathophysiology.^[67] Additionally, in sepsis, CCR4 influences innate immune responses and has been highlighted as a potential diagnostic and therapeutic target based on single-cell analyses.^[68] CCR4 contributes to neuropathic pain in inflammatory conditions, where its expression on immune cells promotes nociceptive transmission and chronic pain states associated with neuropathies.^[69] Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the CCR4 gene associated with increased risk of allergic diseases; for instance, variants near CCR4 are linked to milk allergy susceptibility, highlighting its genetic contribution to Th2-biased immune dysregulation up to 2025 analyses.^[70] Animal models underscore CCR4's therapeutic potential in Th2-driven inflammation. In ovalbumin (OVA)-induced asthma models, CCR4 blockade with antagonists like compound 8a or antibodies reduces airway eosinophilia, Th2 cytokine production, and bronchial hyperreactivity by inhibiting Th2 cell recruitment to the lungs.^[71] Similarly, CCR4-deficient mice or those treated with CCR4 inhibitors show diminished Th2 responses and inflammation in OVA-sensitized airways, confirming CCR4's non-redundant role in allergic lung pathology.^[72]

Clinical and Therapeutic Applications

As a Drug Target

CCR4 serves as a compelling drug target in oncology due to its mediation of regulatory T cell (Treg) recruitment into tumor microenvironments via ligands CCL17 and CCL22, where blockade diminishes Treg infiltration and thereby potentiates effector T cell-mediated anti-tumor immunity.^[2] In allergic conditions, CCR4 antagonism inhibits the migration of Th2 cells to inflamed sites, mitigating exaggerated type 2 immune responses that drive diseases such as atopic dermatitis and asthma.^[2] Preclinical validation of CCR4 targeting has been demonstrated in multiple models, including murine xenografts of adult T-cell leukemia/lymphoma and breast cancer, where antagonists or antibodies reduced tumor growth by depleting Tregs and limiting metastasis.^[73] Similarly, in hepatocellular carcinoma models, CCR4 inhibition curtailed tumor invasion, while orally bioavailable small-molecule antagonists like FLX475 blocked Treg trafficking into solid tumor microenvironments, enhancing overall anti-tumor efficacy across various syngeneic models.^[74] For allergic inflammation, CCR4-deficient mice or antagonist-treated models of atopic dermatitis exhibited reduced Th2 cell infiltration and ameliorated skin lesions, and CCR4 blockade in asthma models attenuated airway leukocyte recruitment and eosinophilic responses.^[73] Targeting CCR4, however, encounters significant challenges, including on-target effects that disrupt normal immune homeostasis, such as lymphopenia and increased infection risk from broad Treg depletion, alongside dermatological toxicities like skin rashes observed in preclinical and early clinical settings.^[2] The receptor's capacity for biased signaling—wherein ligands like CCL17 and CCL22 preferentially activate distinct pathways such as G protein coupling versus β-arrestin recruitment—necessitates selective modulators to minimize off-target impacts on non-pathogenic immune trafficking while preserving therapeutic potency.^[35] Structural investigations in 2024 have illuminated intracellular allosteric sites on CCR4, including pockets involving residues K310^8.49, Y304^7.53, and M243^6.36, which accommodate small-molecule inhibitors like GSK2239633A and enable probe-confined dynamic mapping for refined drug design.^[19] Complementary 2024 studies differentiated class-I and class-II allosteric antagonists, with class-I binders (e.g., C021) showing superior inhibition of chemotaxis and tumor progression in cutaneous T-cell lymphoma xenografts compared to C-terminal site modulators.^[75] Additionally, CCR4 expression emerges as a potential biomarker for immunotherapy response, as elevated levels correlate with enhanced immune cell infiltration, including CD8+ T cells, and improved prognosis in head and neck squamous cell carcinoma, suggesting utility in stratifying patients for Treg-depleting or checkpoint therapies.^[76]

Developed and Investigational Therapies

Mogamulizumab (Poteligeo®), a defucosylated humanized monoclonal antibody targeting CCR4, represents the primary approved therapy modulating this receptor. It enhances antibody-dependent cellular cytotoxicity (ADCC) against CCR4-expressing cells, particularly regulatory T cells (Tregs) and malignant T cells. Initially approved in Japan in 2012 for relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mogamulizumab received FDA approval on August 8, 2018, for adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy, indicating its role in cutaneous T-cell lymphoma (CTCL).^[77]^[78] This approval was supported by the phase III MAVORIC trial, which showed a median progression-free survival of 7.7 months with mogamulizumab versus 3.1 months with vorinostat, establishing its efficacy in CCR4-positive CTCL subtypes.^[79] The safety profile of mogamulizumab includes manageable adverse events, with infusion-related reactions occurring in 33-89% of patients across trials, often grade 1-2 and mitigated by premedication with antihistamines and corticosteroids. Other common events encompass rash (up to 63%), diarrhea, and lymphopenia, with no new safety signals observed in long-term follow-up up to five years.^[80]^[81]^[82] In real-world settings, the drug maintains this tolerability, supporting its use in relapsed settings.^[83] As of October 2025, global registry data from the PROCLIPI study demonstrated a meaningful overall survival benefit for mogamulizumab compared to brentuximab vedotin in patients with advanced CTCL.^[84] Additionally, a phase 2 trial of mogamulizumab combined with CHOP chemotherapy in older patients with aggressive ATLL reported improved 1-year progression-free survival as of September 2025.^[85] Investigational applications of anti-CCR4 antibodies, including mogamulizumab (formerly KW-0761), extend to solid tumors through Treg depletion to enhance antitumor immunity. Phase Ia/Ib trials in CCR4-negative solid cancers demonstrated safe Treg reduction without significant toxicity, prompting phase II evaluations in various solid tumor cohorts as of 2023-2025.^[86]^[87] Ongoing phase I/II studies explore mogamulizumab combinations, such as with histone deacetylase inhibitors or chemotherapy, for CTCL and ATLL, while phase II trials assess its role in peripheral T-cell lymphoma.^[88] No FDA-approved small-molecule CCR4 antagonists exist, though investigational compounds like GSK2239633A reached phase I for asthma but were discontinued due to limited efficacy; recent structure-based designs target intracellular allosteric sites for novel modulators in preclinical stages.^[19] Emerging preclinical efforts focus on bispecific antibodies and CAR-T cells targeting CCR4 to boost ADCC via NK cell engagement, with phase I trials of autologous CCR4 CAR-T cells underway for T-cell malignancies, emphasizing long-term safety monitoring for replication-competent lentivirus.^[89]^[90] These approaches aim to overcome resistance in CCR4-positive tumors, though clinical translation remains early as of 2025.^[2]

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Apr 19, 2021 · The human CC chemokine receptors (CCRs) CCR4, CCR7 and CCR10 play important roles in T cell trafficking and have been reported to display biased agonism.
[27]
https://www.sciencedirect.com/science/article/pii/S0024320519302267
[28]
Chemokine Signaling Pathways - R&D Systems
To date, 18 conventional chemokine receptors have been identified including 1 C chemokine subfamily receptor (XCR1), 10 CC chemokine subfamily receptors (CCR1- ...
[29]
Identification of a non-canonical chemokine-receptor pathway ...
Jan 22, 2024 · CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by ...<|control11|><|separator|>
[30]
Biased Agonism at Chemokine Receptors - PMC - PubMed Central
AOP-RANTES is β-arrestin-biased agonist, which rapidly induces CCR5 ... Dominance of CCL22 over CCL17 in induction of chemokine receptor CCR4 desensitization and ...Biased Chemokine Signaling · Functional Effects Of... · Table 1
[31]
Internalization of the chemokine receptor CCR4 can be evoked by ...
CHO cells were transfected with CCR4 cDNA from human basophils (Power et al., 1995) in the pCIN4 vector; stable transfectants were selected and cultured in ...2.2. Cell Lines · 3. Results · 3.4. Ccr4 Receptors Couple...
[32]
Systematic Assessment of Chemokine Signaling at ... - MDPI
As expected, FlpInCHO cells stably expressed N-terminally cMyc-tagged CCR4ΔC29 at a level 25-fold higher than full-length CCR4, as assessed by ELISA (Table 2).Missing: SNP rs2228672
[33]
CCR4 and CCR7 differentially regulate thymocyte localization with ...
Jun 2, 2023 · CCR4 and CCR7 promote medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets in mice.Missing: cross- talk
[34]
[PDF] Profiling chemokine signalling bias of CCR4, CCR7 and CCR10
1997), and their signalling through CCR4 is thought to be ... Similarly, evaluation of Gi-protein recruitment by CCR7 in response to CCL21 indicated.<|control11|><|separator|>
[35]
Targeting chemokine receptors in disease – a case study of CCR4
... (Power et al., 1995). The original report assigned CCL3 as a functional ligand for CCR4, inducing Ca2+ influx in Xenopus oocytes although this may be an ...
[36]
CCR4 - an overview | ScienceDirect Topics
CCR4 and CCR6 are chemokine receptors expressed on specific immune cells; CCR4 is primarily found on Th2 and Treg lymphocytes, while CCR6 is predominantly ...
[37]
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CCR4 is tissue enhanced in lymphoid tissue and urinary bladder, detected in some tissues, and is part of the Lymphoid tissue - Cytokine signaling cluster.Missing: database | Show results with:database
[38]
A Key Role for Cc Chemokine Receptor 4 in Lipopolysaccharide ...
The CCR4 knockout mice were viable, appeared to develop normally, and showed no overt morphological or behavioral defects in the unstressed state. RT-PCR was ...Missing: species | Show results with:species
[39]
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[40]
ERK/STAT3 activation through CCL17/CCR4 axis-mediated type 2 ...
Mar 30, 2024 · The CCL17/CCR4 axis mediates CDR via the ERK/STAT3 pathway in Th2 cells and type 2 cytokine-induced keratinocyte apoptosis.
[41]
Eosinophil recruitment is dynamically regulated by interplay among ...
Sep 24, 2018 · First, we demonstrated that CCR4 is expressed on eosinophils, and CCL17 and CCL22 could recruit eosinophils directly (Fig. 3b–d).
[42]
https://doi.org/10.4049/jimmunol.166.1.103
[43]
The abnormal expression of CCR4 and CCR6 on Tregs in ...
Specific expression of CCR4 on Treg cells may allow their migration toward APCs and activated T cells leading to inhibition of APC function or suppression of ...
[44]
https://doi.org/10.1084/jem.194.6.847
[45]
A Key Role for Cc Chemokine Receptor 4 in Lipopolysaccharide ...
Our data reveal an unexpected role for CCR4 in the inflammatory response leading to LPS-induced lethality.
[46]
Absence of CCR4 Exacerbates Skin Inflammation in an Oxazolone ...
They observed impaired homing of CCR4-deficient Tregs to the skin and concluded that this would be the reason for spontaneous inflammation seen in the skin of ...
[47]
https://doi.org/10.1084/jem.191.10.1755
[48]
Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively ...
Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse ...
[49]
Recruitment and Expansion of Tregs Cells in the Tumor ...
Furthermore, numerous reports have highlighted the role of CCR4 in the recruitment of Tregs in human tumors, such as breast, ovarian, colon, gastric, lung, ...
[50]
Macrophage CCL22 expression promotes lymphangiogenesis in ...
Mar 16, 2021 · CCL22 attracts Th2 cells via CCR4 increasing Th2 cytokines [e.g., interleukin (IL)-4], which leads to the increased expression of CCL22 in M2- ...
[51]
A CCR4 antagonist reverses the tumor-promoting microenvironment ...
Jan 30, 2017 · CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid ...
[52]
The role of the CCL22-CCR4 axis in the metastasis of gastric cancer ...
Sep 24, 2014 · Omental milky spots are a congenial microenvironment for peritoneal free gastric cancer cells to migrate, survive, and establish cell cluster- ...
[53]
Clinical significance of CCR4 expression in adult T-cell ... - PubMed
Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome · Authors.
[54]
Revised Adult T-Cell Leukemia-Lymphoma International Consensus ...
Jan 18, 2019 · CCR4 is expressed in neoplastic cells in approximately 90% of ATL cases and mutated in 26%. This expression has been associated with cutaneous ...
[55]
Expression of CCR3 and CCR4 Suggests a Poor Prognosis in ...
May 2, 2019 · Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients.Missing: overexpression | Show results with:overexpression
[56]
Deciphering Treg accumulation in melanoma. - ASCO
Conclusions: These data strongly suggest that enhanced homing of CCR4+ Tregs towards the ligand CCL22 is likely involved in accumulating Tregs at melanoma tumor ...
[57]
Regulatory T cells in solid tumor immunotherapy: effect, mechanism ...
Apr 11, 2025 · High Foxp3+ Treg infiltration paradoxically associates with improved survival in colorectal, esophageal and head/neck cancers but worse ...
[58]
Single-Cell Analysis Reveals Characterization of Infiltrating T Cells ...
Jan 21, 2021 · This study aimed to characterize the tumor-infiltrating T cells in moderately differentiated colorectal cancer.Missing: CCR4 2020s
[59]
A degradatory fate for CCR4 suggests a primary role in Th2 ... - NIH
CCR4 is the sole receptor for the chemokines CCL22 and CCL17. Clinical studies of asthmatic airways have shown levels of both ligands and CCR4+ Th2 cells to ...3. Results · 3.3. Ccr4 Undergoes... · 4. Discussion
[60]
CCR4 + memory CD4 + T lymphocytes are increased in peripheral ...
The frequency of CCR4+ cells among CD4+ T cells in the lesional skin of patients with AD was significantly higher than that of patients with psoriasis (51% ± 6% ...
[61]
The C-C chemokine receptors CCR4 and CCR8 identify airway ... - JCI
Virtually all T cells express IL-4 and CCR4. CCR8 is coexpressed with CCR4 on 28% of the T cells, while CCR3 is expressed on eosinophils but not on T cells.<|control11|><|separator|>
[62]
Increased CCR4 expression on circulating CD4+ T cells in ...
Our results showed that the percentage of CD4+/CCR4+ T cells was significantly elevated in AS and RA patients as compared with normal controls. The percentage ...
[63]
CCR4 plays a pivotal role in Th17 cell recruitment and expansion in ...
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Effect of CC chemokine receptor 4 antagonism on the ... - PNAS
Aug 3, 2012 · The results thus indicate that CCR4 is a potential therapeutic target in EAE, and eventually MS. Therapeutic strategies to target DC-specific CCR4 are not yet ...
[65]
CCR4-dependent regulatory T cell function in inflammatory bowel ...
CCR4−/− T reg cells fail to protect development of colitis in vivo. To determine the importance of CCR4 in T reg cell in vivo function, we performed the mouse ...
[66]
Role of the Chemokine Receptors CXCR3 and CCR4 in Human ...
Feb 15, 2005 · The chemokine receptors CXCR3 and CCR4 have recently been described as playing a pivotal role in the mouse model of bleomycin-induced fibrosis.
[67]
[PDF] Genome-wide association study on longitudinal and cross-sectional ...
Feb 20, 2025 · In contrast, the GWAS of milk allergy showed associations at the CTLA4 and CCR4 loci, but not in the MHC region. CTLA4 is known as the ...
[68]
A new antagonist for CCR4 attenuates allergic lung inflammation in ...
Nov 8, 2017 · Our study demonstrated that CCR4 blockaded by compound 8a effectively attenuated airway hyperresponsiveness, airway eosinophilia and Th2 cytokines.
[69]
Blockade of CCR4 in a humanized model of asthma reveals a ...
Jun 1, 2009 · Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyperreactivity ...
[70]
CC Chemokine Receptor 4 (CCR4) as a Possible New Target for ...
The review notes a significant role of CCR4 in nociceptive transmission, especially in painful neuropathy, which accompanies many diseases. The pharmacological ...
[71]
CCR4 Antagonists Inhibit T reg Trafficking into the Tumor ...
Sep 10, 2018 · Tregs are recruited to tumor tissues via chemokines, such as CCL22 binding to CCR4 expressed by Tregs. They appear to expand and become ...
[72]
Small-Molecule CCR4 Antagonists in Cutaneous T-cell Lymphoma
Studies have found that malignant T cells in MF/SS are skin-homing T cells, and they exhibit Th2 and Treg phenotypes and highly express CCR4. Macrophage- ...
[73]
CCR4 is a prognostic biomarker and correlated with immune ...
CCR4 expression level is an independent prognostic factor. CCR4 is positively correlated with immune infiltration and immune checkpoints expression levels.Missing: SNP rs2228672
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Mogamulizumab: a new tool for management of cutaneous T-cell ...
Feb 7, 2019 · First approved in Japan for ATLL in 2012, mogamulizumab (KW-0761) is a defucosylated humanized IgG1κ monoclonal antibody. Its approval in Japan ...
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FDA approves mogamulizumab-kpkc for mycosis fungoides or ...
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[76]
[PDF] 761051Orig1s000 - accessdata.fda.gov
Aug 8, 2018 · This review team recommends regular approval of mogamulizumab (POTELIGEO) for the ... CTCL and ATL. Figure excerpted from Applicant's ...<|separator|>
[77]
Safety and efficacy profile of mogamulizumab (Poteligeo) in the ...
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[78]
Safety & Adverse Reactions | POTELIGEO® (mogamulizumab-kpkc)
POTELIGEO has a consistent safety profile with up to 5 years of data · No increase in rates of infusion reaction from primary analysis · No new safety or ...
[79]
Defucosylated Anti-CCR4 Monoclonal Antibody (KW-0761) for ...
Mar 10, 2012 · The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases.<|separator|>
[80]
Efficacy and manageable toxicity of mogamulizumab in a real-world ...
May 28, 2025 · Mogamulizumab, a CCR4-targeting monoclonal antibody, is FDA-approved for relapsed cutaneous T-cell lymphoma and has shown efficacy in Japanese ...
[81]
Treg-targeted cancer immunotherapy with the humanized anti ...
Sep 20, 2023 · CCR4 expression was examined by immunohistochemistry (IHC) using an anti-CCR4 mAb (KM2160; Kyowa Kirin) and confirmed by a review committee ...
[82]
Anti-CCR4 [KW-0761 (Mogamulizumab)] - Absolute Antibody
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[83]
NCT01611142 | Study of KW-0761 (Mogamulizumab) in Subjects ...
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[84]
Identifying highly active anti-CCR4 CAR T cells for the treatment of T ...
Jul 12, 2023 · Key Points. CCR4 CAR is active against T-cell lymphoma.Fratricide induced by CCR4 CAR selectively depletes Th2, Th17, and Treg while sparing ...
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https://ashpublications.org/blood/article/146/12/1440/537311/A-phase-2-trial-of-CHOP-with-anti-CCR4-antibody