CDC20-Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Inactivating mutations in Polybromo 1 (PBRM1) correlate with positive responses to immune checkpoint inhibitors in clear cell renal cell carcinoma (ccRCC).
• The role of PBRM1 in immunotherapy efficacy for patients with wild-type PBRM1 and its protein stability regulation remain underexplored.

Purpose of the Study:

• To investigate the potential of targeting PBRM1 to enhance immunotherapy efficacy in ccRCC.
• To elucidate upstream pathways regulating PBRM1 protein stability.
• To develop a novel therapeutic strategy for ccRCC patients with wild-type PBRM1.

Main Methods:

• PBRM1 knockdown was performed to assess its impact on macrophage polarization and anti-PD-1 immunotherapy efficacy in renal cell carcinoma (RCC).
• The role of CDC20 in PBRM1 ubiquitination and degradation via selective autophagy was investigated.
• A bicyclic peptide (PB1-p62) was designed to target PBRM1 and p62, facilitating PBRM1 degradation.

Main Results:

• PBRM1 knockdown promoted M1 macrophage polarization and infiltration, enhancing anti-PD-1 immunotherapy efficacy.
• CDC20 was identified as a catalyst for K27 ubiquitination of PBRM1, promoting its degradation through p62-mediated selective autophagy.
• The PB1-p62 peptide successfully promoted PBRM1 degradation, leading to enhanced anti-PD-1 immunotherapy efficacy and improved overall survival in mouse tumor models.

Conclusions:

• Targeting PBRM1 degradation via the PB1-p62 peptide offers a novel strategy to enhance anti-PD-1 immunotherapy in RCC patients with wild-type PBRM1.
• This approach demonstrates potential for clinical application in improving treatment outcomes for RCC.
• The study provides new insights into PBRM1 regulation and its role in the tumor immune microenvironment.