Zodiac (Case 6): CD27 as A Biomarker for Immunotherapy

This is the 7th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.

CD27 as a target for immunotherapy has been under investigation recently, such as the CDX-1127 (Celldex Therapeutics) monoclonal antibody. Recent phase I study (http://www.celldex.com/docs/ASCOPoster2014finalversion_Lymphoid-Malignancies.pdf) shows that complete response (CR) or stable disease (SD) has been achieved in patients with late-stage pre-treated lymphoma (CR on Hodgkin, and SD on non-Hodgkin and follicular).

I did a quick look up of CD27 in Zodiac (www.compgenome.org/zodiac). See my blog here for an introduction of Zodiac. Typing CD27, CD70, PDCD1, CD274, I Zodiac-ed four genes, CD27 and CD70 (the receptor of CD27), and PDCD1 (PD-1) and its ligand CD274 (PD-L1). First, CD27 and its receptor CD70 is co-expressed in Zodiac. Also, there appears to be a co-expression between CD70 and PD-1, the well-known immune checkpoint gene. These results in Zodiac supports the current enthusiasm in using anti-CD27 in combination of PD-1 inhibitor as immunotherapy for cancer treatment.  (see Figure below).

fig1

I then Zodiac-ed CD27 alone (http://compgenome.org/TCGA/index.php?&Gene1=CD27&fdr=0.01&pf1=GE&pf2=GE#gohere) and checked the top 20 genes that are co-expressed with CD27. Strikingly, 9 out of these 20 genes are related to T-cell biology, immunology, or blood biology. Most other genes do not have a known function.

  • CXCR3 This gene encodes a G protein-coupled receptor with selectivity for three chemokines, termed CXCL9/Mig (monokine induced by interferon-g), CXCL10/IP10 (interferon-g-inducible 10 kDa protein) and CXCL11/I-TAC (interferon-inducible T cell a-chemoattractant). Binding of chemokines to this protein induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration.
  • CD8B The CD8 antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes that mediates efficient cell-cell interactions within the immune system. The CD8 antigen, acting as a coreceptor, and the T-cell receptor on the T lymphocyte recognize antigens displayed by an antigen presenting cell (APC) in the context of class I MHC molecules. The functional coreceptor is either a homodimer composed of two alpha chains, or a heterodimer composed of one alpha and one beta chain. Both alpha and beta chains share significant homology to immunoglobulin variable light chains.
  • GRAP2 This gene encodes a member of the GRB2/Sem5/Drk family. This member is an adaptor-like protein involved in leukocyte-specific protein-tyrosine kinase signaling. Like its related family member, GRB2-related adaptor protein (GRAP), this protein contains an SH2 domain flanked by two SH3 domains. This protein interacts with other proteins, such as GRB2-associated binding protein 1 (GAB1) and the SLP-76 leukocyte protein (LCP2), through its SH3 domains.
  • C1QB This gene encodes a major constituent of the human complement subcomponent C1q. C1q associates with C1r and C1s in order to yield the first component of the serum complement system. Deficiency of C1q has been associated with lupus erythematosus and glomerulonephritis. C1q is composed of 18 polypeptide chains: six A-chains, six B-chains, and six C-chains. Each chain contains a collagen-like region located near the N terminus and a C-terminal globular region. The A-, B-, and C-chains are arranged in the order A-C-B on chromosome 1.
  • GZMA Cytolytic T lymphocytes (CTL) and natural killer (NK) cells share the remarkable ability to recognize, bind, and lyse specific target cells. They are thought to protect their host by lysing cells bearing on their surface ‘nonself’ antigens, usually peptides or proteins resulting from infection by intracellular pathogens. The protein described here is a T cell- and natural killer cell-specific serine protease that may function as a common component necessary for lysis of target cells by cytotoxic T lymphocytes and natural killer cells.
  • CD48 This gene encodes a member of the CD2 subfamily of immunoglobulin-like receptors which includes SLAM (signaling lymphocyte activation molecules) proteins. The encoded protein is found on the surface of lymphocytes and other immune cells, dendritic cells and endothelial cells, and participates in activation and differentiation pathways in these cells. The encoded protein does not have a transmembrane domain, however, but is held at the cell surface by a GPI anchor via a C-terminal domain which maybe cleaved to yield a soluble form of the receptor.
  • TNFSF13B The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptors TNFRSF13B/TACI, TNFRSF17/BCMA, and TNFRSF13C/BAFFR. This cytokine is expressed in B cell lineage cells, and acts as a potent B cell activator. It has been also shown to play an important role in the proliferation and differentiation of B cells.
  • RHOH The protein encoded by this gene is a member of the Ras superfamily of guanosine triphosphate (GTP)-metabolizing enzymes. The encoded protein is expressed in hematopoietic cells, where it functions as a negative regulator of cell growth and survival. This gene may be hypermutated or misexpressed in leukemias and lymphomas. Chromosomal translocations in non-Hodgkin’s lymphoma occur between this locus and B-cell CLL/lymphoma 6 (BCL6) on chromosome 3, leading to the production of fusion transcripts. Alternative splicing in the 5′ untranslated region results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2013]
  • FERMT3 Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2010]

It is clear that CD27 interacts with many important genes related to immune cells, such as T-cells, leukocytes (white blood cells), and B-cells. Discoveries of the above from Zodiac could lead to future investigation of additional therapeutic targets.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s