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

• Published in: Cell reports (Cambridge) 2024-04, Vol.43 (4), p.114003-114003, Article 114003
• Main Authors: Peng, Linyuan, Zhou, Liang, Li, Huan, Zhang, Xin, Li, Su, Wang, Kai, Yang, Mei, Ma, Xiaoyu, Zhang, Danlan, Xiang, Siliang, Duan, Yajun, Wang, Tianzhi, Sun, Chunmeng, Wang, Chen, Lu, Desheng, Qian, Minxian, Wang, Zhongyuan
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigen Presentation - immunology; antigen processing and presentation; antitumor immunity; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; CP: Cancer; CP: Immunology; Hippo pathway; Hippo Signaling Pathway; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Humans; immune checkpoint blockade; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MHC class I; Mice; Mice, Inbred C57BL; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; NLRC5; NuRD complex; Protein Serine-Threonine Kinases - metabolism; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; TAZ; TEAD; Transcription Factors - metabolism; YAP; YAP-Signaling Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114003

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the 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 report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer. [Display omitted] •YAP/TEAD inhibits NLRC5 transcription to dampen MHC class I neoantigen presentation•The NuRD complex is required for the YAP/TEAD-repressed expression of MHC class I APP genes•Inhibition or depletion of YAP improves antitumor immunity through NLRC5-MHC class I axis Peng et al. show that the YAP/TEAD complex cooperates with the NuRD complex to repress NLRC5 transcription, thus impairing the MHC class I APP pathway and CD8+ CTL-mediated killing of cancer cells. They provide a rationale for inhibiting YAP activity in immunotherapy for cancer.