UCSF researchers identify therapeutic target to boost antitumor immunity
New findings indicate potential strategy to improve radiation therapy for glioblastoma, other cancers
The immunosuppressive microenvironment of glioblastomas remains a challenge for current brain tumor treatments.
Researchers at UC San Francisco have now found that an enzyme called protein phosphatase 2A (PP2A) plays an important role in mediating the antitumor response of macrophages – an abundant immune cell population in many types of cancer including brain tumors.
Their results, recently published in The Journal of Clinical Investigation, suggest a potential therapeutic strategy using drugs that inhibit the enzyme to activate key inflammatory signals in the tumor microenvironment. This enhanced antitumor immune response could also synergize with current radiation therapies and emerging immunotherapies.
“Macrophages are abundant in multiple types of cancers and usually they're very bad: they promote tumor growth and suppress the T cell function to attack the tumor,” said Rongze “Olivia” Lu, PhD, an assistant professor in the Department of Neurological Surgery and the study’s lead author. “But those macrophages are also very flexible and can become antitumor immune cells.”
Dying cells release DNA into the cytosol that is processed into c-GAMP, which in turn activates macrophages and generates an immune response through the STING-Type I interferon signaling pathway. In cancer, the Type I interferon cytokine works to redirect the T cells to attack the tumor cells as a response to radiation therapy.
Other preclinical studies previously showed that drugs stimulating the STING protein create more antitumor immunity. But then recent clinical trials with these drugs failed to show a benefit for patients with cancer. Lu and her colleagues, including UCSF pediatric neurosurgeon Winson Ho, MD, now think they have found out why.
The researchers found that in these tumor-associated macrophages, the PP2A enzyme blocks the activation of STING. PP2A stabilizes another signaling pathway – known as YAP/TAZ – that acts in opposition to Type I Interferon and its antitumor activity.
This study, Lu says, is the first to identify this YAP/TAZ signaling pathway in tumor-associated macrophages from both mouse and human glioblastoma samples, providing new preclinical insights to help develop novel macrophage-based cancer therapy. Additionally, they found that the B regulatory subunit of the PP2A enzyme regulates how much YAP/TAZ is in the macrophages.
“Our work suggests that targeting PP2A in tumor-associated macrophages is a promising strategy to enhance anti-tumor response,” Lu said. “I am also very grateful to have the funding support for this work from the DOD Peer Reviewed Cancer Research Program and an NIH R01 grant.”
As her research group continues studying the enzyme, Lu is interested in distinguishing how its role may vary between the microglia and the macrophages, which have different cell origins. Lu is also investigating the many types of macrophages and microglia in the brain tumor microenvironment.
With funding from an NIH Special Programs of Research Excellence (SPORE) Developmental Research Program, Lu’s lab is working on developing methods to deliver to the brain drugs that increase the antitumor immune response by inhibiting the PP2A enzyme.
In the meantime, Lu and her colleagues are now looking towards initiating a clinical trial for glioblastoma patients at the UCSF Brain Tumor with PP2A inhibitor alone or combine with radiation, immune checkpoint blockade or STING agonist. “Our long-term goal is to translate our lab research to patients with this devastating disease,” she said.
Ho WS, Mondal I, Xu B, Das O, Sun RC, Chiou P, Cai X, Tahmasebinia F, Wu CY, Wu Z, Matsui W, Lim M, Meng Z, Lu RO. PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages. J Clin Invest. 2023 Feb 9:e162139. doi: 10.1172/JCI162139. Epub ahead of print.