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

Wang, Z.; Qian, M.

doi:10.1101/2023.02.25.530003

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bioRxiv · 10.1101/2023.02.25.530003

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

Wang, Z.·Qian, M.

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Abstract

Many 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.

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Wang, Z., Qian, M.. 2023-02-25. YAP-controlled MHC I and CXCL10 expression potentiates antitumor immunity independently of IFNγ signaling. https://doi.org/10.1101/2023.02.25.530003

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