PD-L1  is a protein that acts as a kind of “brake” to keep immune responses under control.  One way cancer cells defend against tumor-killing immune cells is to load up their cell surface with PD-L1. Now, a team of UCLA Jonsson Comprehensive Cancer Center researchers report they have identified a strategy to break down tumor cell-surface PD-L1 to make tumors more susceptible to immune attack. Their approach combined with other existing therapies may improve treatment responses to metastatic melanoma and other cancers by suppressing resistance.

Their findings are published in the journal Cancer Discovery in a paper titled, “Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance,” and led by Roger S. Lo, MD, PhD, professor of medicine and molecular and medical pharmacology at UCLA’s David Geffen School of Medicine.

“MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance,” wrote the researchers. “Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby promoting T-cell activation.”

Lo and the team at his lab first found that tumor cell-surface PD-L1 is destabilized or degraded by a protein named ITCH.

By utilizing the National Institutes of Health library, the researchers discovered and deployed a small molecule, which they characterized to be an ITCH activator.

By activating ITCH, the small molecule degrades tumor cell-surface PD-L1. When used together with an existing therapy, the small molecule suppresses relapses of melanoma in animal models.

Reducing the accumulation of PD-L1 clears the path for tumor-killing T-cells to do their work. “Once ITCH is activated, it’s now able to degrade or destabilize tumor surface PD-L1,” Lo explained. “And once PD-L1 is degraded, then there are more T cells active to help therapies work better.”

Therapy targeting the MAPK pathway for patients with metastatic cutaneous melanoma is associated with a high rate of response. However, the disease often comes back in a process called acquired resistance.

“In prior work from our group, we found that melanoma cells treated with MAPK-targeted therapy accumulate PD-L1 on their 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 cell-surface PD-L1, then we have the first clue as to how to reduce PD-L1 protein levels in cancers treated with MAPK-targeted therapy.”

In collaboration with another UCLA team led by James Wohlschlegel, PhD, professor of biological chemistry at the David Geffen School of Medicine, Yang identified ITCH as the protein that binds to surface PD-L1 and tags it biochemically for degradation by the tumor cell.

“We were excited to go further to find a potential path for this knowledge to help patients with cancers. Identification of a small molecule that can activate ITCH became a priority,” added Yan Wang, a first-year PhD student who joined the Lo Lab from the department of molecular and medical pharmacology.

PD-L1 “is regarded as a universal tumor-evasive mechanism,” Lo said, and therefore a therapy that degrades it could potentially have wide applications in the immuno-oncology space. He points out that the MAPK pathway is one of the most dysregulated cancer pathways, especially in aggressive cancers like melanoma and pancreatic cancer. “This study advances our knowledge of how to combine mutation- and immune-targeted therapies for patients with cancers.”

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