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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• The Major Histocompatibility Complex class I (MHC class I) pathway is crucial for anti-tumor immunity, presenting antigens to CD8+ T cells.
• Dysregulation of this pathway in cancer hinders effective immunotherapy responses.

Purpose of the Study:

• To investigate the role of the tumor-intrinsic Hippo pathway in regulating MHC class I antigen processing and presentation (APP).
• To explore the potential of targeting the Hippo pathway for enhancing anti-cancer immunity.

Main Methods:

• Correlation analysis of Hippo pathway activation with MHC class I APP gene expression and CD8+ T cell infiltration in mouse and human tumors.
• Investigating the mechanism of YAP/TEAD complex interaction with the nucleosome remodeling and deacetylase complex.
• Assessing the impact of YAP/TEAD inhibition on NLRC5 transcription and MHC class I APP gene expression.

Main Results:

• Tumor-intrinsic Hippo pathway activation positively correlates with MHC class I APP gene expression and CD8+ T cell abundance.
• Inhibition of the Hippo pathway effector YAP/TEAD significantly enhances anti-tumor immunity.
• YAP/TEAD represses NLRC5 transcription; YAP/TEAD depletion or inhibition upregulates NLRC5, boosting MHC class I APP and CD8+ T cell-mediated killing.

Conclusions:

• The Hippo pathway, via YAP/TEAD, impairs the MHC class I APP pathway by repressing NLRC5, thus promoting tumor growth.
• Inhibiting YAP activity presents a promising therapeutic strategy to improve immunotherapy efficacy in cancer.