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.
Biofabrication methods capable of
generating complex, three-dimensional,
cell-laden hydrogel geometries are often challenging technologies
to implement in the clinic and scaled manufacturing processes. Hydrogel
injection molding capitalizes on the reproducibility, efficiency,
and scalability of the injection molding process, and we adapt this
technique to biofabrication using a library of natural and synthetic
hydrogels with varied crosslinking chemistries and kinetics. We use
computational modeling to evaluate hydrogel library fluid dynamics
within the injection molds in order to predict molding feasibility
and cytocompatibility. We evaluate the reproducibility of hydrogel
construct molding and extraction and establish criteria for the selection
of hydrogels suitable for injection molding. We demonstrate that hydrogel
injection molding is capable of generating complex three-dimensional
cell-laden construct geometries using diverse hydrogel materials and
that this platform is compatible with primary human islet encapsulation.
These results highlight the versatility and feasibility of hydrogel
injection molding as a biofabrication technique with potential applications
in the clinic and biomanufacturing.
A major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon CD4 + and CD8 + T cell activation and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap 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 implicatesYap as a mediator of global T cell responses in the tumor microenvironment and as a key 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 inhibiting Yap activity improves T cell responses in cancer.
The development of biomaterial-based therapeutics to induce immune tolerance holds great promise for the treatment of autoimmune diseases, allergy, and graft rejection in transplantation. Historical approaches to treat these immunological...
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