YAP1-Driven PLCβ1 Impairs MHC-I Antigen Presentation and Limits Anti-Tumor Immunity in Gastrointestinal Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) shows promise in cancer therapy but faces challenges in gastrointestinal malignancies due to immunosuppressive tumor microenvironments.
• Understanding mechanisms of immune evasion is crucial for improving ICB efficacy in these cancers.

Purpose of the Study:

• To identify key drivers of immune evasion and ICB resistance in gastrointestinal cancers.
• To elucidate the molecular mechanisms underlying PLCβ1-mediated immune escape.
• To evaluate the therapeutic potential of targeting the identified pathway.

Main Methods:

• Investigated the role of phospholipase C beta 1 (PLCβ1) in gastrointestinal cancer progression and ICB resistance.
• Examined the interaction between PLCβ1 and ERC1, and its effect on NF-κB signaling and MHC-I expression.
• Assessed the upstream regulation of PLCβ1 by the YAP1 complex.
• Utilized YAP inhibitors and anti-PD-1 therapy in preclinical models (syngeneic mice, patient-derived xenografts).

Main Results:

• PLCβ1 was identified as a driver of immune evasion, not direct tumor cell survival, in gastrointestinal cancers.
• PLCβ1 promotes ERC1 degradation, suppressing NF-κB-dependent MHC-I expression and impairing antigen presentation.
• The YAP1 complex directly activates PLCβ1 transcription; YAP inhibition restores MHC-I expression.
• YAP inhibition combined with anti-PD-1 therapy demonstrated synergistic antitumor effects in preclinical models.
• High PLCβ1 expression correlated with reduced patient responsiveness to immunotherapy.

Conclusions:

• The YAP1-PLCβ1-MHC-I axis represents a critical mechanism for immune escape in gastrointestinal cancers.
• Targeting this axis, particularly through YAP inhibition, offers a promising strategy to enhance immunotherapy responsiveness.