A recent study conducted by researchers at NYU Langone Health’s Perlmutter Cancer Center and the University of Oxford has revealed insights into the workings of an immune cell surface receptor known as PD-1. The study indicates that treatments that restrict PD-1’s action can potentially be strengthened to improve their anticancer effect. Furthermore, the same findings support experimental treatment strategies for autoimmune diseases where the immune system attacks the body. Stimulating the action of PD-1, instead of restricting it, can potentially block an overactive immune response.
The body’s immune system is primed to attack virally infected and cancerous cells without harming normal cells. To spare normal cells from immune attack, the system uses “checkpoints” – sensors on the surface of immune cells, including T cells, which turn them off or dampen activation when they receive the right signal. Tumors are seen as abnormal by the immune system, but cancer cells can hijack checkpoints to turn off immune responses.
PD-1 is one of the most important checkpoints, and it is shut down by new drug class called checkpoint inhibitors to make tumors “visible” again to immune attack. These drugs are somewhat effective in a third of patients with various cancers, but the field is seeking ways to improve their performance and scope.
PD-1 signaling is slowed down in autoimmune diseases like rheumatoid arthritis, lupus, and type 1 diabetes, which causes the action of unchecked immune cells to create inflammation that can damage tissues. Agonists, drugs that stimulate PD-1, are now showing promise in clinical trials.
The study found that PD-1 forms a dimer through interactions of its transmembrane segment. This finding is in sharp contrast to other immune receptors, which typically form dimers through the segment of the receptor that is outside the cell. Further 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. Lowering transmembrane dimerization decreased PD-1’s ability to inhibit immune cell activity.
“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 study lead investigator 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.
“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,” said study co-senior investigator and cancer immunologist Jun Wang, PhD. Wang is an assistant professor in the Department of Pathology at NYU Grossman and Perlmutter.
“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 study co-senior investigator and structural biologist Xiang-Peng Kong, PhD. “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,” said Kong, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman and Perlmutter.
Among the study’s other 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.
Funding support for the new study was provided by National Institutes of Health grants R01AI125640, R37CA273333, T32AR069515, and T32GM007308. Additional funding support was provided by NYU Grossman School of Medicine, Kennedy Trust for Rheumatology Research grant 100262Z/12/Z; Research Council of Norway grant 275466, in conjunction with Marie Sklodowska-Curie Actions; Wellcome Trust grant 108869/Z/15/Z; the Melanoma Research Alliance; and a pilot award from the NYU Colton Center for autoimmunity. Wang has been a paid consultant to RootPath Genomics, Bristol Myers Squibb, and Hanmi Pharmaceutical and is a founder, equity holder, and consultant to Remunix. These interests and relationships are being managed in accordance with the policies of NYU Langone Health.
Besides Philips, Wang, and Kong, other NYU Langone researchers involved in this study are colead investigator Jia Liu, and coinvestigators Charles Ng, Ian Ahearn, Ruimin Pan, Christina Luo, Alexander Leithner, Zhihua Qin, and Dan Littman, who is also a Howard Hughes Medical Institute investigator. Other study coinvestigators include Audun Kvalvaag, at Oslo University, Norway; Alexander Morch and co-senior investigator Michael Dustin, at the University of Oxford, United Kingdom; Anna Tocheva, at the Icahn School of Medicine at Mount Sinai in New York; Hong Liang and Yong Zhou, at the University of Texas in Houston; Antonio Garcia-Espana, at the University of Rovira i Virgili in Tarragona, Spain; and Adam Mor, at Columbia University in New York.
