PKCα inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability

• Main Authors: Jiaojiao Yu (Author), Yujin Xiang (Author), Yuzhen Gao (Author), Shan Chang (Author), Ren Kong (Author), Xiaoxi Lv (Author), Jinmei Yu (Author), Yunjie Jin (Author), Chenxi Li (Author), Yiran Ma (Author), Zhenhe Wang (Author), Jichao Zhou (Author), Hongyu Yuan (Author), Shuang Shang (Author), Fang Hua (Author), Xiaowei Zhang (Author), Bing Cui (Author), Pingping Li (Author)
• Format: Book
• Published: Elsevier, 2024-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2211-3835; 10.1016/j.apsb.2024.08.003
• Keywords: Protein kinase C; PD-L1; β-TRCP; Degradation; Immune evasion; Immunotherapy; Therapeutics. Pharmacology; RM1-950
• Source: Acta Pharmaceutica Sinica B, Vol 14, Iss 10, Pp 4378-4395 (2024)

Protein kinase C α (PKCα) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKCα inhibition enhances CD8+ T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKCα as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKCα inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo. Clinical analysis revealed that PKCα expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKCα, identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKCα in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.