CCR4

Overview

First described 1995. 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". Source.

• 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.