YAP-controlled MHC-I and CXCL10 expression potentiates antitumor immunity independently of IFNγ signaling

Abstract

AbstractMany efforts are underway to improve immune checkpoint blockade (ICB) therapy including potentiating MHC-I antigen processing and presentation. Accumulating evidence links the Hippo pathway to immunotherapy response, but the understanding of how the tumor-intrinsic Hippo signaling regulating antitumor immunity is limited. Here, we report that inhibition of the Hippo pathway coactivator YAP in tumor cells increases the expression of genes involving in MHC-I antigen processing and presenting machinery (APM) and CXCL10, promoting robust tumor-infiltrating of cytotoxic CD8+T lymphocytes (CTLs) and overcoming tumor resistance to anti-PD1 ICB therapy. Mechanically, we find that YAP/TEAD complex directly binds and recruits NuRD complex to the NLRC5 promoter to repress NLRC5 transcription, thereby blunting MHC-I antigen presentation. Patient cohort analysis revealed that YAP expression negatively correlated with the expression of NLRC5 and MHC-I APM and intratumoral infiltration of CTLs. Collectively, our results suggest that a novel tumor- promoting function of YAP depends on NLRC5 to impair MHC-I antigen processing and presentation and provide a rationale for inhibiting YAP activity in ICB therapy for cancer.