YAP is a novel regulator of CD4+ and CD8+ T cells during activation, differentiation, and anti-tumor immunity

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Abstract Advanced understanding of T cell regulation has fueled cancer immunotherapy, but durable responses remain confined to a minority of patients. Poor responses can be linked to either suppressed T cell function in tumors or “cold” tumors that exclude immune cells. Identifying novel T cell regulators involved in these processes is a high priority. Our studies identified the protein YAP as a novel regulator of T cells. YAP mRNA and protein were rapidly expressed after T cell activation in mouse CD4+ and CD8+ T cells. T cell-specific Yap knockout (YapKO) generated CD4+ and CD8+ T cells that express elevated levels of activation markers (CD25, CD44, CD69) compared to WT cells. YapKO increased the sensitivity of T cells to anti-CD3 dose, and increased CD4+ T cell differentiation efficiency under Th1, Th2, Th17, and Treg skewing conditions. YapKO CD8+ T cells expanded >20-fold more than WT when cultured in engineered hydrogel matrices optimized for T cell expansions and adoptive transfer. Syngeneic tumors grown in T cell YapKO mice had impaired growth and increased immune infiltration compared to tumors in WT hosts. Co-adoptive transfer of YapKO and WT CD8+ T cells showed only YapKO cells infiltrated B16F10 tumors. RNAseq of CD4+ and CD8+ T cells from tumors and draining lymph nodes showed gene expression changes including upregulation of T cell receptor and cytokine signaling pathways in YapKO hosts. T cells from tumor-draining lymph nodes were not significantly different between YapKO and WT. YapKO gene signatures correlated with immune infiltration and survival in multiple human cancers in TCGA. Our data demonstrated YAP is a novel regulator of diverse T cell functions and may be a useful target for enhancing responses to cancer immunotherapy.