CCR4 Gene Editing    

The chemokine receptor CCR4 is a candidate GPCR that could contribute to medullary entry and central tolerance. In the periphery, CCR4 is predominantly expressed by T reg cells, Th2 cells, and skin-homing T cells. CCR4 is associated with Th2-mediated allergic disorders, such as atopic dermatitis and asthma, and in mature T cell malignancies. CCR4 also promotes interactions of activated T cells with DCs in secondary lymphoid tissues. In the thymus, CCR4 is expressed on post-positive selection thymocytes, and its ligands CCL17 and CCL22 are expressed by myeloid cells in the medulla. CCR4 induces chemotaxis of CD4SP thymocytes in vitro. In conclusion, these studies implicate a role for CCR4 in thymocyte medullary entry and tolerance induction.

CCR4 and Cancer

CCR4 and its ligands CCL17 and CCL22 are modulators of immune responses, especially those mediated by regulatory T cells (Tregs) and TH2 cells. In ovarian cancer CCR4+Tregs migrate towards CCL22 produced by tumor cells or tumor microenvironment, thus creating favorable conditions for tumor growth. High levels of Treg cells were detected in a variety of solid tumors such as colorectal, esophageal, breast, lung, gastric and liver cancer and melanoma. CCR4 is associated with high tumor recurrence and poor prognosis in gastric cancer patients.

Cutaneous and brain-metastasizing melanoma variants stimulated with the CCR4 ligand CCL22, showed a differential AKT phosphorylation pattern. The expression of this chemokine receptor was regulated by the brain microenvironment, because the brain derived-soluble factors upregulated CCR4 expression in melanoma cells. In addition, highly malignant vemurafenib (BRAFmt inhibitor)-resistant human melanoma cells expressed high levels of CCR4. CCL17 and CCL22 expression was upregulated in several organs including liver, lung and brain of the tumor-bearing nude mice harboring these highly malignant tumors. Lee et al. showed that CCR4 is expressed in 17.0% primary gastric cancers and is associated with poor prognosis of gastric cancer patients. In the metastatic 4T1 mouse mammary carcinoma model, Olkhanud et al. found that only CCR4-positive tumor cells had the ability to transfer to the lung, and that strategies that target CCR4 could efficiently control lung metastasis.

CCR4 and Drug development

The dominant expression of CCR4 in Th2 cells makes it a potential therapeutic target for allergic diseases such as AD and asthma. Moreover, due to the expression of CCR4 on Treg cells, CCR4 blockade may also be useful to enhance the efficacy of cancer vaccines. Therefore, many small-molecule CCR4 antagonists have been generated and evaluated in animal models of allergic diseases, some giving highly promising results. However, most compounds are still in a preclinical state.

The frequent expression of CCR4 in ATL and CTCLs also makes it a possible therapeutic target for these T-cell neoplasms. Thus, Kyowa Hakko Kogyo generated a chimeric antibody KM2760—from the mouse anti-CCR4 mAb KM2160 and a human IgG1. KM2760 showed highly enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in vitro and efficient antitumor activity against CCR4-expressing leukemic cells in vivo. In addition, a group from Harvard University also generated a humanized monoclonal anti-CCR4 antibody mAb2-3 and showed a potent antitumor effect against a CTCL cell line in vitro and in vivo as well as inhibition of Treg cell chemotaxis and Treg-mediated suppression of effector T-cell proliferation.

CCR4 Gene Editing Services

CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively CCR4 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• CCR4 Gene Knockout: We offer CCR4 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service covers from sgRNA design and construction, pronuclear microinjection to Founders genotyping and breeding.
• CCR4 Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop CCR4 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of CCR4 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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