CD27 Gene Editing

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CD27 Gene Editing    

CD27 is a member of the TNF-superfamily, including both costimulatory and apoptosis-inducing molecules. CD27 is expressed on a wide range of lymphocytes, including B-cells, T-cells and natural killer (NK)-cells. CD27 plays a critical role in diverse immunological processes, including the survival, activation and effector functions of T cells, as well as the proliferation and cytotoxic activity of NK cells. Acute down-regulation of CD27 occurs by internalization and shedding while transcriptional inhibition of CD27 occurs in well-differentiated effector cells. In many tumors, CD27 is still expressed on infiltrating lymphocytes (TIL) and can transmit signals to relevant T and NK cells.

CD27–CD70 Pathway

The only characterized ligand of CD27 is CD70 (TNFSF7), a TNF superfamily member, which is expressed on activated T lymphocytes, B lymphocytes, NK cells and dendritic cells, and also weakly on activated macrophages. Similar to other TNF family members, CD70 has retrograde signal transduction ability, and thus CD27-CD70 interactions have bidirectional functional effects. CD70 surface expression is initiated by coordinated signals from components of innate and adaptive immunity, and is usually not visible in the absence of CD80/CD86 costimulatory molecules. The expression of CD70 is regulated by metalloprotease cleavage and internalization after binding with CD27. Recent studies have suggested that regulatory T cells can also cut off CD70 from DC, defining a novel pathway for reducing DC function in the tumor microenvironment.

 CD27-CD70 pathway in immune regulation. Figure 1. CD27-CD70 pathway in immune regulation. (Han B K, et al., 2016)

Members of the TNFRSF like CD27 frequently present as key costimulatory T-cell receptors to generate a functional immune response. The costimulatory T-cell signal through CD27 further enhances cell division and cell survival, as well as effector functions like cytokine production, especially IP-10, or cytotoxicity by activating different pathways such as the nuclear factor-κB, phosphatidylinositol 3-kinase or protein kinase B. Thus, CD27/CD70 costimulation has the potential to boost the immunity by T-cell activation, increased clonal expansion and enhanced differentiation into antigen specific cytotoxic and memory T cells. Besides, CD27/CD70 also has the capability of influencing the innate immune system by inducing proliferation and cytotoxicity by increased interferon-gamma (IFN-γ) production of NK cells. About the B-cell lineage, in vitro studies suggested that T cells that are expressing CD27 and CD70 play a key role in regulating B-cell activation and immunoglobulin synthesis.

CD27 as a Therapeutic Target in Tumor Therapy

CD27 is a costimulatory T-cell receptor, which is essential for optimal T-cell priming and memory differentiation. Especially in the activation of cytotoxic CD8+ T cells, CD27 signalling plays an important immunological role, potentially usable for antitumour therapy. The CD27 ligand CD70 is restrictively expressed on activated immune cells and is usually absent in non-lymphoid normal tissue. In various lymphoid malignancies such as diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), and mantle cell lymphoma, a constitutive expression of CD70 has been described. CD70 expression was frequently observed in several solid cancers including pancreatic, lung, breast, colon, ovarian, renal cancer, melanoma and glioblastoma. In addition, the importance of CD27/CD70 signalling for anticancer immunity is underscored by the observation that patients with germ line, somatic mutations or deletions in CD27 or CD70 more frequently develop Hodgkin lymphoma or DLBCL. Therefore, targeting of the CD27/CD70 axis could be of therapeutic potential.

Motivated by the data indicating that CD27 costimulation strongly enhances T-cell responses against tumors and virus infections, several groups investigated the anti-tumor therapeutic efficacy of agonistic anti-CD27 antibodies. French et al. demonstrated that the mouse CD27-specific rat mAb AT124-1 has in the BCL1 lymphoma model an anti-tumor activity comparable to those of the initially investigated anti-CD40 antibody. Follow up studies in the poorly immunogenic B16 melanoma model further confirmed that the efficacy of the AT124-1 therapy is due to the enhanced activity of tumor infiltrated CD8+ T-cells and NK cells. T-cell dependent anti-tumor activity has also been found with an independent non-depleting agonistic CD27 antibody. There is also experimental evidence that agonistic CD27 antibodies improve the efficacy of dendritic cell-based anti-tumor vaccination protocols. In human CD27 transgenic mice, it has been proved that the anti-human CD27 antibody 1F5 (CDX1127, Varlilumab), which is currently investigated in clinical trials, has also strong T-cell costimulatory activity.

CD27 Gene Editing Service

CRISPR/Cas9 PlatformCB, 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 CD27 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

  • CD27 Gene Knockout: We offer CD27 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.
  • CD27 Gene Knockin: CRISPR/Cas9 PlatformCB provides the one-stop CD27 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of CD27 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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References

  1. Bullock T N J. Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer. Current opinion in immunology, 2017, 45: 82-88.
  2. Han B K, et al. The CD27–CD70 pathway and pathogenesis of autoimmune disease. Seminars in Arthritis and Rheumatism. WB Saunders, 2016, 45(4): 496-501.
  3. Grant E J, et al. The role of CD27 in anti-viral T-cell immunity. Current opinion in virology, 2017, 22: 77-88.
  4. Wajant H. Therapeutic targeting of CD70 and CD27. Expert opinion on therapeutic targets, 2016, 20(8): 959-973.
  5. Starzer A M, Berghoff A S. New emerging targets in cancer immunotherapy: CD27 (TNFRSF7). ESMO open, 2020, 4(Suppl 3): e000629.
  6. Thomas L J, et al. Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity. Oncoimmunology, 2014, 3(1): e27255.
For research use only. Not intended for any clinical use.

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