{"entity":{"id":"ccr4","kind":"target","name":"CCR4","aka":[],"tldr":"CCR4 is a chemokine receptor on skin-homing and regulatory T cells, and on the malignant cells of cutaneous T-cell lymphoma and adult T-cell leukaemia; mogamulizumab removes those cells.","summary":"CCR4 binds CCL17/CCL22 and marks Th2 and regulatory T cells and most CTCL, Sézary and ATLL cells. Mogamulizumab (afucosylated anti-CCR4) depletes them by ADCC (MAVORIC). Because it also depletes Tregs, CCR4 blockade is being combined with checkpoint inhibitors in solid tumours (small molecules FLX475, mogamulizumab-nivolumab), so far with modest results. CCR4 gain-of-function mutations occur in ~25% of ATLL.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/CCR4_(gene)","links":[{"label":"MAVORIC (Lancet Oncol 2018)","url":"https://doi.org/10.1016/S1470-2045(18)30379-6"},{"label":"Kim et al., Lancet Oncol 2018: MAVORIC, mogamulizumab against vorinostat in previously treated cutaneous T-cell lymphoma","url":"https://doi.org/10.1016/S1470-2045(18)30379-6"},{"label":"Kataoka et al., Nat Genet 2015: integrated molecular analysis of 426 adult T-cell leukaemia/lymphoma cases","url":"https://doi.org/10.1038/ng.3415"}],"tags":["gap-fill"],"related":[],"cancers":["peripheral-t-cell-lymphoma","non-hodgkin-lymphoma"],"sections":[],"technologies":["monoclonal-antibody"],"targets":[],"drugs":["mogamulizumab"],"companies":[],"institutions":[],"pathways":["oncogenic-viruses","inflammation-nfkb"],"terms":["adcc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: More than 80% of mycosis fungoides and Sezary syndrome, about 90% of adult T-cell leukaemia/lymphoma, and a subset of peripheral T-cell lymphoma. Also on healthy cells: Skin-homing T cells, T-helper-2 and T-helper-17 cells, and regulatory T cells; the Human Protein Atlas reads CCR4 as lineage enriched in T cells (61 nTPM). What the medicine does: Mogamulizumab is defucosylated, which raises its affinity for the Fc receptor on natural killer cells and makes antibody-dependent cytotoxicity its main mechanism. MAVORIC randomised 372 patients with previously treated mycosis fungoides or Sezary syndrome to mogamulizumab or vorinostat and is the trial the approval rests on (Kim 2018). How tumours lose it: CCR4 is itself mutated in about a quarter of adult T-cell leukaemia/lymphoma cases, with gain-of-function truncations of the cytoplasmic tail; whether that changes antibody binding is not settled. What that costs the patient: Depletion of regulatory T cells along with the tumour, which causes rash and raises the risk of autoimmune complications, and a real and specific problem before an allogeneic transplant: mogamulizumab given shortly before transplant has been associated with severe graft-versus-host disease, because the regulatory T cells that would have restrained it are gone.","Lymphoma, HTLV-1, Tax and HBZ: Human T-lymphotropic virus 1 integrates into the genome of a CD4 T cell and expresses Tax, which switches on NF-kB and interferes with the DNA-damage response and the spindle checkpoint, and HBZ, encoded on the opposite strand, which is retained when Tax expression is switched off under immune pressure. The host genome then acquires the rest of the lesions, and they are not random: the alterations found across 426 cases overlap significantly with the proteins Tax itself binds, and are concentrated in T-cell receptor and NF-kB signalling, T-cell trafficking and immune surveillance, with activating mutations in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7, CTLA4-CD28 and ICOS-CD28 fusions, and intragenic deletions of IKZF2, CARD11 and TP73 (Kataoka 2015). Frequency: Across 426 adult T-cell leukaemia/lymphoma cases analysed by whole-genome, exome, transcriptome and targeted sequencing with copy-number and methylation arrays (Kataoka 2015). Most people infected with HTLV-1 never develop the disease, and the latency between infection, usually in infancy through breastfeeding, and the leukaemia is measured in decades. What it changes about treatment: The CCR4 finding is the practical one: CCR4 is both frequently expressed and frequently mutated, and mogamulizumab is used in this disease. The virus itself is not a drug target, and antiretroviral treatment does not cure the leukaemia."],"symbol":"CCR4","role":[],"sources":[],"specificity":"lineage-antigen","distribution":"one-type","specificityNote":"Lineage antigen shared with normal T-cells: HPA blood lineage lineage enriched at or above 25 nTPM, and 1 antibody (Mogamulizumab) aim at it, so normal cells of the lineage are hit too. HPA CCR4: RNA tissue enhanced (lymphoid tissue 12 nTPM, urinary bladder 5 nTPM); blood lineage lineage enriched (T-cells 61 nTPM); no normal tissue stained high. Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Lymphoma); Open Targets associates it with 2 specific cancer types at or above 0.5 (mycosis fungoides, Sezary syndrome); the corpus evidence decides and the Open Targets list is quoted for comparison. (Rule 5 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas CCR4 tissue","url":"https://www.proteinatlas.org/ENSG00000183813-CCR4/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas CCR4 pathology","url":"https://www.proteinatlas.org/ENSG00000183813-CCR4/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000183813 associations","url":"https://platform.opentargets.org/target/ENSG00000183813/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:1605","ensembl":"ENSG00000183813","uniprot":"P51679","entrez":"1233","firstDescribed":1995,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Power C.A. et al, J. Biol. Chem, 1995, \"Molecular cloning and functional expression of a novel CC chemokine receptor cDNA from a human basophilic cell line\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/7642634/","biology":"GPCR expressed on Th2, Th17 and Treg cells and skin-homing T cells; chemotaxis to CCL17/CCL22 produced by dendritic cells and keratinocytes.","whereFound":["Mycosis fungoides / Sézary syndrome (>80%)","Adult T-cell leukaemia/lymphoma (~90%; 25% mutated)","Peripheral T-cell lymphoma (subset)","Tumour-infiltrating Tregs in solid tumours"],"targetClass":"surface-antigen","prevalence":[{"cancerId":"peripheral-t-cell-lymphoma","pct":88.3,"measure":"IHC, CCR4 on tumour cells in adult T-cell leukaemia/lymphoma (91 of 103 patients)","source":"https://pubmed.ncbi.nlm.nih.gov/14506150/","note":"ATLL subtype only. PTCL-NOS is heterogeneous (Ishida 2004, doi:10.1158/1078-0432.CCR-04-0371) and the MAVORIC CTCL approval did not require CCR4 testing"}]},"route":"/targets/ccr4/","neighbours":{"cancer":[{"id":"cutaneous-t-cell-lymphoma","kind":"cancer","name":"Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome)","route":"/cancers/cutaneous-t-cell-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"peripheral-t-cell-lymphoma","kind":"cancer","name":"Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)","route":"/cancers/peripheral-t-cell-lymphoma/"},{"id":"sezary-syndrome","kind":"cancer","name":"Sezary syndrome","route":"/cancers/sezary-syndrome/"}],"technology":[{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"}],"drug":[{"id":"mogamulizumab","kind":"drug","name":"Mogamulizumab","route":"/drugs/mogamulizumab/"}],"pathway":[{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"},{"id":"oncogenic-viruses","kind":"pathway","name":"Oncogenic viruses","route":"/pathways/oncogenic-viruses/"}],"term":[{"id":"adcc","kind":"term","name":"ADCC (antibody-dependent cellular cytotoxicity)","route":"/terms/adcc/"},{"id":"lymphoma-bio-htlv1","kind":"term","name":"HTLV-1, Tax and HBZ in adult T-cell leukaemia/lymphoma","route":"/terms/lymphoma-bio-htlv1/"},{"id":"lymphoma-bio-lineage-antigen-cost","kind":"term","name":"What it costs to aim at a lineage antigen","route":"/terms/lymphoma-bio-lineage-antigen-cost/"}],"company":[{"id":"kyowa-kirin","kind":"company","name":"Kyowa Kirin","route":"/companies/kyowa-kirin/"}]}}