Immune Checkpoint Discovery Has Implications for Treating Cancer and Autoimmune Diseases

Posted on March 28th, 2024 by Dr. Monica M. Bertagnolli

Your immune system should ideally recognize and attack infectious invaders and cancerous cells. But the system requires safety mechanisms, or brakes, to keep it from damaging healthy cells. To do this, T cells—the immune system’s most powerful attackers—rely on immune “checkpoints” to turn immune activation down when they receive the right signal. While these interactions have been well studied, a research team supported in part by NIH has made an unexpected discovery into how a key immune checkpoint works, with potentially important implications for therapies designed to boost or dampen immune activity to treat cancer and autoimmune diseases.¹

The checkpoint in question is a protein called programmed cell death-1 (PD-1). Here’s how it works: PD-1 is a receptor on the surface of T cells, where it latches onto certain proteins, known as PD-L1 and PD-L2, on the surface of other cells in the body. When this interaction occurs, a signal is sent to the T cells that stops them from attacking these other cells.

Cancer cells often take advantage of this braking system, producing copious amounts of PD-L1 on their surface, allowing them to hide from T cells. An effective class of immunotherapy drugs used to treat many cancers works by blocking the interaction between PD-1 and PD-L1, to effectively release the brakes on the immune system to allow the T cells to unleash an assault on cancer cells. Researchers have also developed potential treatments for autoimmune diseases that take the opposite tact: stimulating PD-1 interaction to keep T cells inactive. These PD-1 “agonists” have shown promise in clinical trials as treatments for certain autoimmune diseases.

However, to fulfill the promise of these approaches for treating cancer and autoimmune diseases, a better understanding of precisely how PD-1 works to suppress T cell activity is still needed. The thinking has long been that individual PD-1 receptors act alone. But, as reported in Science Immunology, it turns out that this may not usually be the case. A team led by Jun Wang and Xiangpeng Kong of New York University Langone Health’s Perlmutter Cancer Center, with Elliot Philips of NYU and Michael Dustin of the University of Oxford, U.K., used sophisticated techniques to look for evidence of what happens when PD-1 proteins work together in pairs.

They found that PD-1’s tendency to link, or not link, with a second PD-1 protein to form what’s known as a “dimer” depends on interactions with portions of the protein that cross the immune cell membrane. They also found that, when PD-1 receptors pair up, they do a better job of squashing immune responses. The findings also showed that a single change in the amino acid structure in the portion of PD-1 that crosses the cell membrane can strengthen or weaken immune responses.

One reason why these fundamental discoveries are exciting is they suggest that interfering with PD-1’s ability to form dimers might make immunotherapy treatments for cancer more effective. In addition, treatments that strengthen interactions between paired PD-1 receptors might aid in the design of promising new drug classes that are intended to tamp down inflammation seen in people with some autoimmune diseases, including rheumatoid arthritis, lupus, and type 1 diabetes. The research team now plans to conduct further investigations of PD-1 blockers and agonists to explore whether these findings could eventually lead to more effective treatments for both cancer and autoimmune diseases.

Reference:

[1] Philips EA, et al. Transmembrane domain-driven PD-1 dimers mediate T cell inhibition. Science Immunology. DOI: 10.1126/sciimmunol.ade6256 (2024).

NIH Support: National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of General Medical Sciences