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

Cell Rep. 2024 Apr 23;43(4):114003. doi: 10.1016/j.celrep.2024.114003. Epub 2024 Mar 23.


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.

Keywords: CP: Cancer; CP: Immunology; Hippo pathway; MHC class I; NLRC5; NuRD complex; TAZ; TEAD; YAP; antigen processing and presentation; antitumor immunity; immune checkpoint blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antigen Presentation* / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Hippo Signaling Pathway*
  • Histocompatibility Antigens Class I* / genetics
  • Histocompatibility Antigens Class I* / immunology
  • Histocompatibility Antigens Class I* / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction*
  • T-Lymphocytes, Cytotoxic / immunology
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins / metabolism


  • Histocompatibility Antigens Class I
  • Protein Serine-Threonine Kinases
  • YAP-Signaling Proteins
  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Transcription Factors
  • NLRC5 protein, mouse