The TSP1-CD47-SIRPα interactome: an immune triangle for the checkpoint era

Abstract

The use of treatments, such as programmed death protein 1 (PD1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies, that loosen the natural checks upon immune cell activity to enhance cancer killing have shifted clinical practice and outcomes for the better. Accordingly, the number of antibodies and engineered proteins that interact with the ligand-receptor components of immune checkpoints continue to increase along with their use. It is tempting to view these molecular pathways simply from an immune inhibitory perspective. But this should be resisted. Checkpoint molecules can have other cardinal functions relevant to the development and use of blocking moieties. Cell receptor CD47 is an example of this. CD47 is found on the surface of all human cells. Within the checkpoint paradigm, non-immune cell CD47 signals through immune cell surface signal regulatory protein alpha (SIRPα) to limit the activity of the latter, the so-called trans signal. Even so, CD47 interacts with other cell surface and soluble molecules to regulate biogas and redox signaling, mitochondria and metabolism, self-renewal factors and multipotency, and blood flow. Further, the pedigree of checkpoint CD47 is more intricate than supposed. High-affinity interaction with soluble thrombospondin-1 (TSP1) and low-affinity interaction with same-cell SIRPα, the so-called cis signal, and non-SIRPα ectodomains on the cell membrane suggests that multiple immune checkpoints converge at and through CD47. Appreciation of this may provide latitude for pathway-specific targeting and intelligent therapeutic effect.

Keywords: CD47; Cancer; Checkpoint; SIRPα; Thrombospondin-1; Type 1 diabetes.

Fig. 1

TSP1-CD47-SIRPα immune checkpoints. CD47 is at the center of multiple immune inhibitory checkpoints: (1) TSP1-CD47 checks T, natural killer and dendritic cells, and perhaps macrophages. (2) Trans CD47-SIRPα checks macrophage phagocytosis. (3) Cis CD47-SIRPα limits inflammation wherever both occur on the same cell. (4) Cis CD47-αMβ2 and cis CD47-VEGFR-2, labeled other cis CD47, check macrophages and T cells, respectively. Acting through cell surface CD47 or SIRPα, the pictured pathways are inhibitory in immune cells. Not pictured are TSP1-SIRPα and ‘reverse’ SIRPα-CD47 signaling [110], which have not been assessed within the checkpoint paradigm. Regarding intracellular effects, SIRPα promotes phosphorylation of SHP1 and SHP2 to quell immune cells [111]. However, SHP1 [112] and SHP2 [113] are activated by other than SIRPα, facts not parsed out in relation to the interactome. Cytoplasmic transmission of the TSP1-CD47 signal is via integrins [114], heterotrimeric G proteins [115], and probably other cell surface molecules. The meager cytoplasmic domain of CD47 encourages this [10]

Fig. 2

Re-thinking CD47 targeting checkpoint inhibition for cancer immunotherapy. A The conventional ‘don’t eat me’ signal mediated by the ‘forward’ negative effect in trans of macrophage-displayed CD47. This signal is postulated to be interfered with by clinical blocking anti-CD47 antibodies. The potential ‘reverse’ effect of macrophage CD47 on tumor-expressing SIRPα is unknown. The TSP1-CD47-SIRPα interactome effect on adaptive immunity is ill-defined. B Current data support a predominantly negative effect on T cells in cis, which may represent a natural mechanism of homeostasis to maintain self-tolerance. It could be reinforced by acting in trans, resulting in an additional tumor escape mechanism. And data suggest that TSP1 interferes with CD47 binding to SIRPα presumably in trans and cis. MΦ, macrophage; TCR, T cell receptor; MHC, major histocompatibility complex; Ag, antigen; mAb, monoclonal antibody