PD-L1 is a protein that acts as a kind of “brake” to keep immune responses under control. One of the ways cancer cells defend themselves against immune cells that kill tumors is to charge their cell surface with PD-L1. Now, a team of researchers at UCLA’s Jonsson Integral Cancer Center reports that it has identified a strategy to break the PD-L1 from the tumor’s cell surface to make tumors more susceptible to immune attack. Its approach combined with other existing therapies may improve treatment responses to metastatic melanoma and other cancers by suppressing resistance.
His findings are published in the journal Cancer Discovery in an article entitled “Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance,” and directed by Roger S. Lo, MD, PhD, Professor of Medicine and Molecular Medicine. medical. pharmacology at the David Geffen School of Medicine at UCLA.
“MAPK inhibitor therapy (MAPKi) in melanoma leads to the accumulation of PD-L1 / 2 on the surface of the tumor, which can evade antitumor immunity and accelerate acquired resistance,” the researchers wrote. “Here, we found that E3 ITCH ligase binds, ubiquitin, and downregulates PD-L1 / L2 from tumor surface to MAPKi-treated human melanoma cells, thereby promoting cell activation. · T cells “.
Lo and his lab team first discovered that PD-L1 on the tumor’s cell surface is destabilized or degraded by a protein called ITCH.
Using the library of the National Institutes of Health, the researchers discovered and deployed a small molecule, which they described as an activator of the ITCH.
By activating ITCH, the small molecule degrades PD-L1 from the tumor cell surface. When used in conjunction with existing therapy, the small molecule suppresses melanoma relapses in animal models.
Reducing PD-L1 accumulation clears the way for tumor-killing T cells to do their job. “Once the itching is activated, it is now able to degrade or destabilize the surface of the PD-L1 tumor,” Lo explained. “And once PD-L1 degrades, there are more active T cells to help make therapies work better.”
MAPK-targeted therapy for patients with metastatic skin melanoma is associated with a high response rate. However, the disease often returns in a process called acquired resistance.
“In our group’s previous work, we found that melanoma cells treated with MAPK-targeted therapy accumulate PD-L1 on the cell surface,” said Zhentao Yang, PhD, a postdoctoral fellow in Lo’s lab. “So we hypothesized that if we find the protein whose normal job is to degrade the PD-L1 cell surface, then we have the first clue on how to reduce PD-L1 protein levels in cancer-treated cancers. directed to MAPK “.
In collaboration with another UCLA team led by James Wohlschlegel, PhD, a professor of biological chemistry at the David Geffen School of Medicine, Yang identified ITCH as the protein that binds to the PD-L1 surface and the labeled biochemically for degradation by the tumor cell.
“We were excited to go further to find a potential path for this knowledge to help cancer patients. Identifying a small molecule that can trigger itching became a priority,” added Yan Wang, a first-year doctoral student who joined the Lo Lab of the department of molecular and medical pharmacology.
PD-L1 “is considered a universal tumor escape mechanism,” Lo said, and therefore a degrading therapy could have wide applications in the space immuno-oncology. He points out that the MAPK pathway is one of the most deregulated cancer pathways, especially in aggressive cancers such as melanoma and pancreatic cancer. “This study advances our knowledge of how to combine mutation-targeted therapies and immunity for cancer patients.”