CD70 molecule
Identifiers
SymbolCD70
Alt. symbolsCD27LG, TNFSF7
NCBI gene970
HGNC11937
OMIM602840
RefSeqNM_001252
UniProtP32970
Other data
LocusChr. 19 p13
Search for
StructuresSwiss-model
DomainsInterPro

CD70 (Cluster of Differentiation 70) is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.[1]

Expression

In physiological condition the expression of CD70 on immune cells is transient and tightly controlled. It is primarily expressed on highly activated T cells and B cells, as well as on NK cells and mature dendritic cells. CD70 expression on T and B cells is stimulated through triggering of T and B cell receptors and can be upregulated by cytokines such as IL-1α, IL-2, IL-12, GM-CSF and TNF-α, while IL-4 and IL-10 can decrease CD70 expression.[2] Expression of CD70 on mDCs and pDCs is induced with Toll-like receptor (TLR) triggering and CD40 ligation.[3] Also, CD70 can be induced on NK cells upon stimulation with IL-15.[4]

Functions

CD70 acts as a costimulatory molecule and plays an important role in the regulation of the immune system activation, specifically by improving T-cell and B-cell activation, proliferation and survival, leading to a more efficient immune response.[5]

CD70 on activated antigen presenting cells (APC) including dendritic cells and B cells binds to CD27 on T lymphocytes and provides costimulatory signals. The interaction between CD27 and CD70 leads to the recruitment of intracellular adaptor proteins, such as TRAF2 and TRAF5, which then activate signaling pathways, including the NF-κB and JNK pathway.[6][7] CD27 signaling stimulates naïve CD4+ T lymphocytes to differentiate into Th1 cells by activation the transcription factor T-bet.[7]

In addition to its role in T-cell activation and proliferation, CD70 also plays a role in the regulation of B-cell activation and differentiation. Receptor engagement can also cause reverse signaling through CD70. CD70 reverse signaling activates the phosphatidylinositol-3 kinase (PI3K) and MAP kinase signaling pathways, leading to the activation of various transcription factors and the expression of genes involved in cell growth and survival.[8]

Clinical significance

Cancer

Some studies have shown that CD70 is overexpressed in several types of cancer, including Hodgkin's lymphoma and non-Hodgkin's lymphoma. CD70 is also found to be overexpressed in some types of solid tumors.[9][10][11] This overexpression of CD70 in cancer cells has been shown to promote cell proliferation and survival, and to inhibit apoptosis, leading to the development and progression of the cancer. It is therefore suggested that anti-CD70 antibodies might be a possible treatment for CD70 positive lymphomas as normal lymphocytes have low CD70 expression.[12]

Drug development

Recent research has focused on the potential therapeutic use of CD70 in cancer treatment. One strategy being investigated is the use of antibodies that target CD70. ARGX-110 is a CD70-specific antibody that is currently under investigation for the treatment of hematological malignancies. It is being developed by the Belgian company arGEN-X. In December 2013 a first part of a phase 1b trial was completed. In January 2014 a safety and efficacy phase of the study started.[13]

Vorsetuzumab mafodotin is a CD70-targeted antibody-drug conjugate that started clinical trials for renal cell carcinoma.[14]

See also

References

  1. ^ "NCBI".
  2. ^ Nolte MA, van Olffen RW, van Gisbergen KP, van Lier RA (May 2009). "Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology". Immunological Reviews. 229 (1): 216–231. doi:10.1111/j.1600-065X.2009.00774.x. PMID 19426224. S2CID 32860864.
  3. ^ Hashimoto-Okada M, Kitawaki T, Kadowaki N, Iwata S, Morimoto C, Hori T, Uchiyama T (2009). "The CD70–CD27 interaction during the stimulation with dendritic cells promotes naive CD4+ T cells to develop into T cells producing a broad array of immunostimulatory cytokines in humans". International Immunology. 21 (8): 891–904. doi:10.1093/intimm/dxp056. hdl:2433/86187. PMID 19556308. Retrieved 8 February 2023.
  4. ^ Vossen MT, Matmati M, Hertoghs KM, Baars PA, Gent MR, Leclercq G, Hamann J, Kuijpers TW, van Lier RA (15 March 2008). "CD27 Defines Phenotypically and Functionally Different Human NK Cell Subsets". The Journal of Immunology. 180 (6): 3739–3745. doi:10.4049/jimmunol.180.6.3739. ISSN 0022-1767. PMID 18322179. S2CID 26953338.
  5. ^ Borst J, Hendriks J, Xiao Y (1 June 2005). "CD27 and CD70 in T cell and B cell activation". Current Opinion in Immunology. Lymphocyte activation / Lymphocyte effector functions. 17 (3): 275–281. doi:10.1016/j.coi.2005.04.004. ISSN 0952-7915. PMID 15886117.
  6. ^ Boursalian TE, McEarchern JA, Law CL, Grewal IS (2009), Grewal IS (ed.), "Targeting CD70 for Human Therapeutic Use", Therapeutic Targets of the TNF Superfamily, vol. 647, New York, NY: Springer New York, pp. 108–119, doi:10.1007/978-0-387-89520-8_7, ISBN 978-0-387-89519-2, PMID 19760069, retrieved 8 February 2023
  7. ^ a b Han BK, Olsen NJ, Bottaro A (1 February 2016). "The CD27–CD70 pathway and pathogenesis of autoimmune disease". Seminars in Arthritis and Rheumatism. 45 (4): 496–501. doi:10.1016/j.semarthrit.2015.08.001. ISSN 0049-0172. PMID 26359318.
  8. ^ Arens R, Nolte MA, Tesselaar K, Heemskerk B, Reedquist KA, van Lier RA, van Oers MH (15 September 2004). "Signaling through CD70 Regulates B Cell Activation and IgG Production". The Journal of Immunology. 173 (6): 3901–3908. doi:10.4049/jimmunol.173.6.3901. ISSN 0022-1767. PMID 15356138. S2CID 31566653.
  9. ^ Junker K, Hindermann W, von EF, Diegmann J, Haessler K, Schubert J (1 June 2005). "Cd70: a new tumor specific biomarker for renal cell carcinoma". Journal of Urology. 173 (6): 2150–2153. doi:10.1097/01.ju.0000158121.49085.ba. PMID 15879877.
  10. ^ Held-Feindt J, Mentlein R (7 March 2002). "CD70/CD27 ligand, a member of the TNF family, is expressed in human brain tumors". International Journal of Cancer. 98 (3): 352–356. doi:10.1002/ijc.10207. ISSN 0020-7136. PMID 11920585. S2CID 12298972.
  11. ^ Hishima T, Fukayama M, Hayashi Y, Fujii T, Ooba T, Funata N, Koike M (May 2000). "CD70 Expression in Thymic Carcinoma". The American Journal of Surgical Pathology. 24 (5): 742–746. doi:10.1097/00000478-200005000-00014. ISSN 0147-5185. PMID 10800994.
  12. ^ Israel BF, Gulley M, Elmore S, Ferrini S, Feng WH, Kenney SC (2005). "Anti-CD70 antibodies: a potential treatment for EBV+ CD70-expressing lymphomas". Mol. Cancer Ther. 4 (12): 2037–44. doi:10.1158/1535-7163.MCT-05-0253. PMID 16373719. S2CID 1821535.
  13. ^ "ARGX-110: first-in-class CD70-targeting antibody with unique mode of therapeutic action". arGEN-X. Archived from the original on 9 March 2015. Retrieved 28 February 2015.
  14. ^ Seattle Genetics Third Quarter 2013 Financial Report[permanent dead link]