# If Plan A Does Not Work: The CD47 Ectodomain as a Target for Immune Tolerance

## TL;DR

This paper explores why targeting the CD47 protein to boost cancer immunity has limited success and suggests exploring its potential in autoimmune diseases instead.

## Contribution

The paper proposes shifting focus from using CD47 as a cancer therapy target to exploring its role in immune tolerance for autoimmune diseases.

## Key findings

- Targeting the CD47 ectodomain for cancer therapy has shown limited clinical success.
- CD47 may have broader physiological roles that limit its effectiveness as a cancer target.
- Alternative approaches (Plan B) could explore CD47's potential in autoimmune disease modulation.

## Abstract

Cell surface immune checkpoint receptors are objects for therapeutic intervention to stimulate immune cell attack of cancers. Interference between the checking ectodomain (ECD) and the natural ligand lowers constitutive restraints exerted on immune cells. This approach assumes that immune cells can do more, that a checkpoint blocker will make immune cells more effective at killing cancer cells, and that checkpoint molecules might have limited physiological roles. These assumptions may be warranted, as in the case of checkpoint-blockers towards the programmed death-ligand 1 (PD-L1) ECD, where clinical outcomes are consistently good. However, this does not appear to be the case for the universally expressed CD47 ECD. Much effort has been directed at engineering molecules that bind to the CD47 ECD to increase T cell and macrophage killing of cancers. But a wealth of clinical data do not indicate strong signals, improved killing, or meaningful survival advantages. This suggests that the CD47 ECD is a subpar target for cancer therapy. Consideration of reasons accounting for the modest benefits realized by molecules that bind to the CD47 ECD in cancer, also known as Plan A, is provided. This is followed by thoughts on what might be done, known as plan B, to identify advantages within the CD47 ECD for modulating tolerance in autoimmune diseases.