NYU Research Reveals the Double Life of Key Immune Checkpoint Protein PD-1

A study published in Science Immunology on March 8, 2024 by researchers at NYU Langone Health’s Perlmutter Cancer Center and the University of Oxford has upended a foundational assumption about one of immunology’s most important proteins — with significant implications for both cancer treatment and autoimmune disease therapy. The study received pilot funding from the Judith and Stewart Colton Center for Autoimmunity at NYU.

The protein in question is PD-1, a checkpoint receptor on the surface of T cells that acts as an off-switch for immune activity. Checkpoint inhibitor drugs that block PD-1 have revolutionized cancer treatment by making tumors visible to immune attack. Meanwhile, drugs that stimulate PD-1 — known as agonists — are now showing promise for dampening the overactive immune responses that drive autoimmune diseases like rheumatoid arthritis, lupus, and type 1 diabetes.

The new study reveals that PD-1 does not function alone as previously assumed, but instead forms pairs — called dimers — through interactions in its transmembrane segment. This challenges the longstanding view that PD-1 operates as a monomer. Crucially, the researchers found that encouraging PD-1 dimerization increases its ability to suppress T cell activity, while disrupting it reduces that suppression. A single change in the protein’s amino acid structure can tip the balance either way.

The findings suggest that future drug development should focus on modulating PD-1 dimerization — strengthening it to treat autoimmune disease, or weakening it to enhance anticancer immunotherapy — rather than exclusively targeting PD-1’s interactions with its signaling ligands, as has been the prevailing approach.