Blocking a protein known for regulating organ size and favoring tumor growth – called YAP – could boost anti-cancer responses and increase the effectiveness of immunotherapies, a new study in mice reports.
The research, “YAP is essential for Treg mediated suppression of anti-tumor immunity,” was published in the journal Cancer Discovery.
Regulatory T-cells (Tregs) are immune cells that work to dampen excessive immune responses, and so prevent an autoimmune disease from developing. However, Tregs’ ability to lower immune system activity also means they can be a barrier to effective anti-cancer immunotherapy, which works by stimulating an immune response against tumor cells.
A protein called Foxp3 plays a key role in controlling the expression of genes relevant to Treg-mediated suppression. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.
Studies have shown that TGF-beta – a type of small protein called cytokine that controls diverse cellular mechanisms, including cell differentiation and growth – may be essential to activate and maintain Foxp3 expression in Tregs.
YAP, for yes-associated protein, is important in the conversion of DNA to RNA in gene expression and as a regulator of organ size. Its levels are commonly higher in some cancer patients — such as those with ovarian, lung, and prostate cancers — where YAP promotes tumor growth. But the effect of YAP on the immune system and cancer responses to treatments that target that system remained unknown.
Researchers at the Johns Hopkins Kimmel Cancer Center earlier reported that, compared to other types of T-cells, Tregs had high YAP protein and RNA levels, a finding they considered unexpected.
Here, they studied mice genetically engineered to specifically lack YAP in their T-cells, including Tregs. Deleting YAP resulted in enhanced inflammatory responses, diminished the production of Tregs under conditions of limited TGF-beta, and weakened the immune suppressive function of Tregs.
And, importantly, the YAP deficiency made Tregs unable to suppress immune responses to tumor growth in an aggressive mouse model of melanoma.
But YAP blocking also boosted the effects of both an anti-tumor vaccine, called GM-Vac, and an anti-PD1 antibody — a type of immunotherapy called a “checkpoint” inhibitor in the diseased mice.
Inhibiting YAP, indeed, was effective in mouse models of various types of cancer, the study reported.
These findings “imply that targeting YAP should be a potent means of overcoming immune suppression in the cancer setting and improving the efficacy of endogenous and therapeutically induced tumor killing,” the researchers wrote.
“As part of an ongoing effort to identify precise mechanisms of Treg generation, maintenance, and function in the context of cancer, we have made the surprising discovery that YAP, a transcription factor critical in developmental regulation of organ size, is in fact an important factor in the generation and function of Tregs,” their study concludes. “The poorly immunogenic tumor [B16 melanoma tumor model] failed to grow in mice with Treg-specific Yap deletion, which displayed markedly enhanced indicators of proinflammatory antitumor immunity compared with WT [wild type mice as] controls.”
While optimistic that targeting YAP could be a new way to fight cancer, they also suggested that the opposite approach – increasing YAP activity – may treat such autoimmune diseases as multiple sclerosis and inflammatory bowel disease.
