Abstract
A major challenge for cancer immunotherapy is sustaining T-cell activation and recruitment in immunosuppressive solid tumors. Here, we report that the levels of the Hippo pathway effector Yes-associated protein (Yap) are sharply induced upon the activation of cluster of differentiation 4 (CD4)-positive and cluster of differentiation 8 (CD8)-positive T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T-cell activation, differentiation, and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T-cell responses in the tumor microenvironment and as a negative regulator of T-cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T-cell biology and suggest that Yap inhibition improves T-cell responses in cancer.
Highlights
Cluster of differentiation 8-positive (CD8+) and cluster of differentiation 4-positive (CD4+) T cells are central players in the adaptive immune system
We observed rapid induction of Yes-associated protein (Yap) protein in both CD4+ and cluster of differentiation 8 (CD8)+ T cells upon in vitro activation (Fig 1A and 1B). This observation contrasted with prior reports that Yap is exclusively expressed in Tregs or CD8+ T cells cultured under specific conditions [27,37], which prompted us to systematically explore roles for Yap in CD4+ and CD8+ T-cell activation and function
Yap expression was efficiently reduced in both CD4+ and CD8+ T cells in Yap-conditional knockout (cKO) mice, which was expected given the activity of this Cre model at the CD4+CD8+ double-positive (DP) stage of T-cell development (S1A and S1B Fig), and cells were efficiently marked by enhanced yellow fluorescent protein (EYFP) expression (S1C and S1D Fig)
Summary
Cluster of differentiation 8-positive (CD8+) and cluster of differentiation 4-positive (CD4+) T cells are central players in the adaptive immune system. T cells elicit targeted, antigen-specific responses for direct killing of an infected or transformed cell, shaping and regulating the immune response in host defense [1]. Most mature T cells circulate in a resting, naïve state, and upon cognate antigen recognition, T cells become activated, proliferate clonally, and differentiate into effector T cells. Naïve CD8+ T cells differentiate into cytotoxic T cells, while CD4+ T cells differentiate into an array of different types of helper (i.e., T helper cell type 1 [Th1], Th2, Th17) or regulatory T cells (Tregs) depending on microenvironmental cues [2].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
