Abstract P174: YAP1 drives immune suppression in urothelial carcinoma of bladder

YAP1 is a principal component of the Hippo pathway and is considered as one of the critical regulators of tumorigenesis. Recent studies indicate that YAP1 can suppress the antitumor immunity and influence the differentiation of regulatory T cells (Tregs) by inducing TGFβ/SMAD pathway, but the mechanisms of YAP1 regulated modulation of tumor immune microenvironment is still in its infancy. Most importantly no study has been reported in YAP1 associated immune suppression in UCB. Here, we used syngeneic mouse models with three different mouse bladder cancer cells (MB49, UPPL595 and BBN 975) and demonstrated that YAP1 amplification upregulates the expression of IL-6 in tumor cells in vitro and in vivo, which in turn directly induces immunosuppressive tumor microenvironment (TME). YAP1 expression in cancer cells significantly induces the infiltration of MDSCs and attenuates the CD8 T cells in tumor tissue. YAP1 upregulation also induces different CXCR2 associated ligands and influences the polarization of naive macrophages into M2 type or tumor associated macrophages. Additionally, YAP1 expression enhances cancer stemness properties in the cancer cells and induces the intracellular accumulation of lipid droplets, which may also be a major factor in the development of immunosuppressive TME. Our pilot in vivo studies also suggest that YAP1 downregulation in the tumor cells can stimulate antitumor adaptive immunity in the host and improve tumor immunogenicity, leading to tumor regression. Overall, our results demonstrated the key role of YAP1 in modulating the TME and establish a potential rationale for targeting YAP1 in combination with checkpoint inhibitors for treating UCB. Citation Format: Pritam Sadhukhan, Mingxiao Feng, Emily Illingworth, Ido Sloma, M. Talha Ugurlu, Fenna Sille, Woonyoung Choi, David J. McConkey, Mohammad Hoque. YAP1 drives immune suppression in urothelial carcinoma of bladder [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P174.