Palmitic acid-triggered B7H3 palmitoylation promotes immune escape

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Colorectal cancer (CRC) with microsatellite stability (MSS) shows limited response to immune checkpoint blockade.
• B7H3 (CD276) is an immune checkpoint protein overexpressed in many tumors, but its stabilization mechanism is unknown.
• Understanding B7H3 regulation is crucial for developing novel CRC immunotherapies.

Purpose of the Study:

• To investigate the mechanism maintaining high B7H3 protein levels in cancer.
• To explore B7H3 palmitoylation as a potential therapeutic target for MSS CRC.
• To evaluate strategies for enhancing anti-tumor immunity against colorectal cancer.

Main Methods:

• Investigated the role of palmitic acid (PA) and ZDHHC24 in B7H3 palmitoylation at cysteine 496.
• Assessed the impact of B7H3 palmitoylation on its interaction with sequestosome 1 (SQSTM1/p62) and subsequent degradation.
• Utilized genetic modifications (C496A mutation, Zdhhc24 deletion) in a colitis-associated colorectal cancer (CAC) mouse model.
• Developed and tested a cell-penetrant peptide targeting the ZDHHC24-B7H3 interaction.
• Evaluated the synergy of the peptide with anti-programmed cell death protein 1 (PD-1) therapy.

Main Results:

• Palmitic acid (PA) promotes B7H3 palmitoylation via ZDHHC24 at cysteine 496, stabilizing B7H3 protein.
• This palmitoylation prevents B7H3 binding to SQSTM1, inhibiting autophagic degradation.
• Stabilized B7H3 suppresses CD8+ T cell antitumor activity.
• Disrupting B7H3 palmitoylation (via C496A mutation or Zdhhc24 deletion) enhances CD8+ T cell responses in a CAC model.
• A peptide blocking ZDHHC24-B7H3 interaction boosts antitumor immunity and synergizes with PD-1 blockade.

Conclusions:

• B7H3 palmitoylation by ZDHHC24 is a key mechanism for B7H3 stabilization, suppressing anti-tumor immunity in colorectal cancer.
• Targeting this metabolic-immune node, specifically B7H3 palmitoylation, represents a promising strategy for enhancing colorectal cancer immunotherapy.
• The developed peptide offers a potential therapeutic approach to overcome resistance to current immunotherapies like PD-1 blockade.