Hippo signaling-controlled MHC-I antigen processing and presentation pathway potentiates antitumor immunity

MHC class I (MHC-I)-mediated tumor antigen processing and presentation (APP) pathway is essential for recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we reported that activation of the tumoral intrinsic Hippo pathway positively correlated with the expression of MHC-I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector YAP/TEAD potently improved antitumor immunity. Mechanistically, the YAP/TEAD complex cooperated with the NuRD complex to repress the NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increased the expression of MHC-I APP genes and enhanced CD8+ CTLmediated killing of cancer cells. Collectively, our results suggest a novel tumorpromoting function of YAP depending on NLRC5 to impair MHC-I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer. Overall design: To elucidate the potential mechanism of Yap in breast cancer, RNA-seq analysis was performed in 4T1 cells to analyze differential expressed genes after Yap knockdown.RNA libraries were prepared for sequencing using standard Illumina protocols.