Boosting cancer immunotherapy by switching off a protein

Regulatory T cells, or Tregs, ensure our immune responses don’t spin out of control and can cause autoimmune diseases. But on the flip side, they can also limit the power of the immune system to fight cancer. Scientists have now found a way to suppress Tregs’ activity, and they believe it will enhance the effectiveness of immuno-oncology treatments.

The key is a protein called the Yes-associated protein (YAP). YAP is a transcriptional regulator known for its role in the Hippo signaling pathway, which controls organ size and apoptosis, or programmed cell death. When activated, it can inhibit apoptosis in cells and can thus lead to the formation of tumors. However, little has been understood about YAP in immune cells until now.

Researchers at the Johns Hopkins Kimmel Cancer Center have found that YAP plays a role in the suppression of Tregs’ anti-tumor activity. They reported their discovery in Cancer Discovery.

The team used a mouse model with Treg-specific YAP deficiency. The mice grew normally, without defects in T-cell development or any immune pathologies. They then challenged the mice with an aggressive form of melanoma and found that YAP-knockout mice controlled the growth of the melanoma cells, while tumors grew fast in normal mice. What's more, the activation of tumor-fighting immune cells in YAP-knockout mice was much less restrained.

There is a YAP inhibitor on the market called verteporfin—an eye drug marketed as Visudyne by Bausch & Lomb. So the Johns Hopkins team tested the drug in mice alone and in combination with either an anti-PD1 or a cancer vaccine called GM-Vac. While all resulted in tumor size reduction in mice, the combination therapies showed better results than the monotherapy did, they reported.

"These findings strongly suggest a major role for Treg-derived YAP in crafting the immunosuppressive nature of the tumor microenvironment. They also suggest the potential of immunotherapeutic approaches that include YAP-targeting agents," wrote the researchers in the study. Because YAP and Tregs are amplified in many human tumor types, the approach could be applied to many cancers, said Fan Pan, M.D., Ph.D., senior author of the study and a Johns Hopkins associate professor of cancer immunology, in a statement.

Many studies are aimed at boosting the efficacy of immuno-oncology agents. A group of scientists at Columbia University Medical Center, for example, recently found that a drug called pentoxifylline, which is used to improve blood circulation, could make checkpoint inhibitors more effective by inhibiting a protein that also potentiates Tregs. And a Massachusetts Institute of Technology spinoff called Torque is planning human trials of a personalized T-cell therapy that uses drug-filled nanoparticles to boost the immune response to cancer.

Pan’s team is optimistic YAP inhibitors could become immuno-oncology agents. They are also interested in exploring the idea that enhancing YAP activity could be useful in treating autoimmune diseases.

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