Targeting WDR12 Unleashes T-Cell-Mediated Antitumor Activity in Melanoma by Destabilizing CD276

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Melanoma is a deadly skin cancer with limited treatment responses.
• Tumors evade immune attack via inhibitory checkpoints, leading to immunotherapy resistance.

Purpose of the Study:

• Identify novel targets for overcoming melanoma immune resistance.
• Investigate the role of WDR12 in immunotherapy failure.

Main Methods:

• Assessed WDR12 expression in melanoma nonresponders.
• Utilized genetic inhibition of WDR12 to evaluate T-cell infiltration and function.
• Determined the mechanism involving WDR12, CCT7, and CD276 (B7-H3) stabilization.
• Identified and tested SU14813, a WDR12 inhibitor, in preclinical models.

Main Results:

• Elevated WDR12 expression correlates with immunotherapy nonresponse.
• WDR12 inhibition boosts intratumoral CD8+ T-cell infiltration and cytotoxic function.
• WDR12 stabilizes CD276, suppressing T-cell activity and promoting immune escape.
• SU14813 reduces CD276 stability and T-cell suppression.
• Combined SU14813 and anti-PD-1 therapy shows superior antitumor efficacy in vivo.

Conclusions:

• A WDR12-CCT7-CD276 axis drives melanoma immune resistance.
• Targeting WDR12 with PD-1 blockade is a promising therapeutic strategy for melanoma.