Signal regulatory proteins (SIRP) are a multigene family of immunoreceptors encoded in humans by a cluster of genes on chromosome 20p13. The family encompasses five members with variable levels of amino acid sequence homology, including SIRPα, SIRPβ1, SIRPγ, SIRPβ2, and SIRPδ. The glycoprotein SIRPα, also known as CD172a, SHPS-1, BIT (rat homolog), p84 (mouse homolog), MFR, MYD-1, or PTPNS1, is the primordial and also the best-conserved member of the family.
| Checkpoint receptor | Alternate name | Pathway |
| SIRPα | CD172a, SHPS-1, BIT, p84, MFR, MYD-1, and PTPNS1 | CD47-SIRPα pathway |
The principal ligand identified for SIRPα is the surface glycoprotein CD47, originally known as integrin-associated protein. Although SIRPα is expressed on all myeloid cells (monocytes, macrophages, granulocytes, myeloid dendritic cells) and neuronal cells in the central nervous system, CD47 is expressed on all normal cells in the body.
The binding of CD47 to SIRPα promotes phosphorylation of tyrosine residues within two typical immunoreceptor tyrosine-based inhibitory motifs (ITIM) encoded within the SIRPα cytoplasmic tail. Subsequently, the phosphorylated ITIM function to recruit and activate protein tyrosine phosphatases (PTPase), in particular the Src homology region 2 (SH2)-domain-containing phosphatase-1 (SHP-1) and 2 (SHP-2). The interaction of the phosphatase SH2-domains to phosphorylated ITIM of SIRPα disrupts their autoinhibitory activity towards the PTPase domain, thereby triggering enzymatic activity. The resulting dephosphorylation of phosphotyrosine residues on various proximal substrates subsequently counterbalances activating signaling pathways depending on tyrosine phosphorylation, thereby restricting phagocytic function.
Fig.1 The CD47/SIRPα myeloid-specific immune checkpoint. (Weiskopf, 2017)
Biologicals that target SIRPα are currently being pursued in parallel to CD47 targeting agents. In vitro and in vivo data suggest that, much like Fc null CD47 blocking antibodies, SIRPα-blocking agents can effectively induce anti-tumor control when used in combination with tumor-opsonizing antibodies. In addition, as SIRPα is only expressed on a restricted number of cell types, targeting the CD47-SIRPα axis with SIRPα-blocking agents does not suffer from the antigen sink issue that has complicated the use of CD47 targeting molecules. Thus, small-molecule inhibition of this pathway may be attractive because of the expected high tissue penetrance of small molecule inhibitors and the potential for oral bioavailability.
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