Checkpoint Dimer May Toggle between Anticancer and Antiautoimmune Action

A study reported by researchers at NYU Langone Health’s Perlmutter Cancer Center and at the University of Oxford has offered up new insights into the workings of an immune cell surface receptor, called PD-1 (programmed cell death-1), which indicate how treatments that restrict its action could potentially be strengthened to improve their anticancer effect. The research, showing that PD-1 can form dimers, may also support experimental treatment strategies for autoimmune diseases—by which the immune system attacks the body—because stimulating this ability of PD-1, as opposed to restricting it, can potentially block an overactive immune response.

“Our goal is to use our new knowledge of the functioning of PD-1 to determine if weakening its dimerization, or pairing, helps make anticancer immunotherapies more effective, and just as importantly, to see if strengthening its dimerization helps in the design of agonist drugs that quiet overactive T cells, tamping down the inflammation seen in autoimmune diseases,” said co-senior investigator and structural biologist Xiang-Peng Kong, PhD, a professor in the department of biochemistry and Molecular Pharmacology at NYU Grossman and Perlmutter. “Presently, research efforts have focused on strengthening PD-1 interactions with its ligands, or signaling molecules, involved with inhibiting T cell action … Our new study suggests that efforts to design better drugs should focus on increasing or decreasing PD-1’s dimerization to manipulate T cell function.”

Kong and colleagues reported on their findings in Science Immunology, in a paper titled “Transmembrane domain—driven PD-1 dimers mediate T cell inhibition.”

The body’s immune system is primed to attack virally infected and cancerous cells while leaving normal cells alone. To spare normal cells from immune attack, the system uses checkpoints, or sensors on the surface of immune cells, including T cells, which dampen or turn cell activity off when the right signal is received. But while the immune system recognizes tumors as abnormal, cancer cells can hijack checkpoints to turn off immune responses.

PD-1 is a key checkpoint, and the target of checkpoint inhibitor drugs that effectively render tumors “visible” again to immune attack. Such drugs are at least somewhat effective in a third of patients with a variety of cancers, say the study authors, but the field is urgently seeking ways to improve their performance and scope.

At the same time, PD-1 signaling is slowed in autoimmune diseases like rheumatoid arthritis, lupus, and type 1 diabetes, such that the action of unchecked immune cells creates inflammation that can damage tissues. Agonists, drugs that stimulate PD-1, are now showing promise in clinical trials.

Many immune checkpoints are receptors on the surface of T cells that act to translate docking information from the outside of the cell to the signaling portion of the receptor inside the cell. Connecting the outside-of-the-cell portion of PD-1 with the inside portion is the transmembrane segment. Many immune receptors function in pairs called dimers, but to date, PD-1 has been thought to function alone—as a monomer—and not in the dimer form.

The newly reported study results showed that PD-1 forms a dimer through interactions of its transmembrane segment. The team suggests this finding is in sharp contrast to that for other immune receptors, which typically form dimers through the segment of the receptor that is outside the cell.

The team’s immune cell testing in mice showed that encouraging PD-1 to form dimers, specifically in the transmembrane domain but not in its outer or inner regions, increased its ability to suppress T cell activity, while decreasing transmembrane dimerization lowered PD-1’s ability to inhibit immune cell activity. “In our study, manipulation of PD-1 TMD dimerization revealed a structure-function relationship whereby PD-1 dimerization potentiates its function,” they noted. “Our data suggest that manipulation of the oligomeric state of the PD-1 axis may offer an additional modality in the effort to enhance cancer immunotherapy or diminish autoimmunity.”

“Our study reveals that the PD-1 receptor functions optimally as dimers driven by interactions within the transmembrane domain on the surface of T cells, contrary to the dogma that PD-1 is a monomer,” said research co-lead and physician-scientist Elliot Philips, MD, PhD, an internal medicine resident at NYU Grossman School of Medicine and Perlmutter Cancer Center. Philips is also an alumnus of the Vilcek Institute of Biomedical Sciences at NYU.

The authors cited results from a recent Phase II clinical trial reporting that Peresolimab, a PD-1 agonist monoclonal antibody, was effective in treating rheumatoid arthritis, but that the mechanism whereby peresolimab acts as an agonist was not reported. “Our characterization of PD-1 TMD dimerization may help inform evolving strategies for developing both agonists and antagonists,” they stated.

Co-senior investigator and cancer immunologist Jun Wang, PhD, an assistant professor in the Department of Pathology at NYU Grossman and Perlmutter, added, “Our findings offer new insights into the molecular workings of the PD-1 immune cell protein that have proven pivotal to the development of the current generation of anticancer immunotherapies, and which are proving essential in the design and developing of the next generation of immunotherapies for autoimmune diseases.”

Among the study’s findings was that a single change in the amino acid structure of the transmembrane segment can act to either enhance or diminish the inhibitory function of PD-1 in immune responses. The team plans further investigations of PD-1 inhibitors and agonists to see if they can tailor what they say are more effective, “rationally designed” therapies for both cancer and autoimmune disorders. Concluding on their findings in their paper, the team wrote, “In this study, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain (TMD) interactions and that propensity for dimerization correlates with PD-1 ability to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.”