Inhibiting Yap for improved T cell activation and anti-tumor immunity

Abstract Immunotherapies have shown promise in the treatment of cancers, but challenges such as sustained T cell activation and recruitment into tumors have prevented their wide-spread success. We have identified Yes-associated-protein (Yap), a transcriptional regulator that plays key roles in mechanotransduction, as an important immunoinhibitory protein. Yap is rapidly induced at the mRNA and protein levels in CD4-posititve and CD8-positive T cells upon activation with mechanical stimuli impacting Yap nuclear-cytoplasmic dynamics. We found that T cell specific deletion of Yap results in enhanced T cell activation, differentiation, and function, which translates in vivo to an improved ability for Yap-deleted T cells to repress solid tumor growth. Strikingly, Yap-deleted T cells showed an enhanced ability to infiltrate solid tumors. Gene expression analyses of Yap-deleted tumor-infiltrating T cells demonstrates Yap as a mediator of T-cell responses in the local tumor microenvironment, and implicates Yap as a negative regulator of T-cell tumor infiltration and patient survival in diverse human cancers. Our observations indicate that Yap plays critical roles in T-cell biology and suggest that Yap inhibition may offer a method for improving T cell recruitment and activation in therapies for solid tumors.