Insights into the operations of a surface receptor on immune cells, known as PD-1, demonstrate potential enhancements in the effectiveness of treatments that limit its activity in combating cancer, as indicated by a recent study. Additionally, these findings lend support to experimental approaches for addressing autoimmune conditions, where the immune system mistakenly targets the body. Stimulating PD-1 activity, instead of inhibiting it, could potentially counteract an overly aggressive immune response.
Conducted by a team of researchers from NYU Langone Health’s Perlmutter Cancer Center and the University of Oxford, the study has been published in the journal Science Immunology.
The study primarily focuses on the immune system’s ability to distinguish and attack virally infected cells while preserving normal ones. To prevent immune cells, particularly T cells, from attacking healthy cells, the system employs “checkpoints” – receptors on the cell surface that regulate or lessen cell activation upon receiving specific signals. Although the immune system recognizes tumors as abnormal, cancer cells can exploit these checkpoints to evade immune responses.
One of the critical checkpoints is the programmed cell death receptor 1 (PD-1) protein, which is deactivated by a relatively recent class of drugs known as checkpoint inhibitors to reinvigorate the immune system’s ability to target tumors. While these drugs exhibit some level of efficacy in around one-third of cancer patients, researchers are actively seeking methods to enhance their performance and broaden their application.
Conversely, in conditions like lupus and type 1 diabetes, PD-1 signaling is impaired, leading to unchecked immune cell activity and consequent tissue inflammation. Clinical trials are now exploring the potential of agonists, which are drugs that stimulate PD-1, in managing these autoimmune disorders.
Many immune checkpoints, including PD-1, are receptors located on T cells’ surfaces that facilitate the transmission of external signals to the receptor’s internal signaling component. Unlike other immune receptors that typically form dimers through their extracellular segments, PD-1 has conventionally been considered to function independently rather than in a dimeric form.
The study findings reveal that PD-1 indeed forms dimers through interactions within its transmembrane segment, contrary to existing beliefs. Further experiments involving immune cells in mice demonstrated that promoting PD-1 dimerization, specifically in the transmembrane domain, enhanced its capacity to suppress T cell activity. Conversely, inhibiting transmembrane dimerization reduced PD-1’s ability to restrain immune cell function.
Lead investigator Dr. Elliot Philips, along with co-senior investigators Dr. Jun Wang and Dr. Xiang-Peng Kong, emphasized the significance of these discoveries in advancing cancer immunotherapies and developing innovative treatments for autoimmune diseases. They highlighted the potential of modulating PD-1’s dimerization to optimize the efficacy of immunotherapies and mitigate inflammation in autoimmune conditions.
The study also identified that a minor alteration in the amino acid composition of the transmembrane segment could either enhance or diminish PD-1’s inhibitory role in immune responses. The research team intends to further explore PD-1 inhibitors and agonists to refine therapeutic approaches tailored for cancer and autoimmune disorders.
For more information, refer to the study titled “Transmembrane Domain Driven PD-1 Dimers Mediate T Cell Inhibition” published in Science Immunology (2024).
Source: ‘Double life’ of key immune protein reveals new strategies for treating cancer and autoimmune diseases (2024, March 8) retrieved 8 March 2024 from https://medicalxpress.com/news/2024-03-life-key-immune-protein-reveals.html