In physiological condition the expression of CD70 on immune cells is transient and tightly controlled. It is primarily expressed on highly activatedT cells andB cells, as well as onNK cells and maturedendritic 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 asIL-1α,IL-2,IL-12,GM-CSF andTNF-α, whileIL-4 andIL-10 can decrease CD70 expression.[2] Expression of CD70 on mDCs and pDCs is induced withToll-like receptor (TLR) triggering andCD40 ligation.[3] Also, CD70 can be induced on NK cells upon stimulation withIL-15.[4]
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 activatedantigen 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 asTRAF2 andTRAF5, which then activate signaling pathways, including theNF-κB andJNK pathway.[6][7] CD27 signaling stimulates naïve CD4+ T lymphocytes to differentiate intoTh1 cells by activation thetranscription factorT-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 thephosphatidylinositol-3 kinase (PI3K) andMAP kinase signaling pathways, leading to the activation of various transcription factors and the expression of genes involved in cell growth and survival.[8]
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]
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 ofhematological malignancies. It is being developed by theBelgian companyarGEN-X. In December 2013 a first part of aphase 1b trial was completed. In January 2014 a safety and efficacy phase of the study started.[13]
