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

• Published in: Acta pharmaceutica Sinica. B 2024-10, Vol.14 (10), p.4378-4395
• Main Authors: Yu, Jiaojiao, Xiang, Yujin, Gao, Yuzhen, Chang, Shan, Kong, Ren, Lv, Xiaoxi, Yu, Jinmei, Jin, Yunjie, Li, Chenxi, Ma, Yiran, Wang, Zhenhe, Zhou, Jichao, Yuan, Hongyu, Shang, Shuang, Hua, Fang, Zhang, Xiaowei, Cui, Bing, Li, Pingping
• Format: Article
• Language: English
• Subjects: Breast cancer; Combination strategies; Degradation; Immune evasion; Immunotherapy; Original; PD-L1; Protein kinase C; β-TRCP
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2024.08.003

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. PKCα inhibitors enhance tumor evasion by maintaining PD-L1 stability, which impairs their tumor-inhibiting effect. The PD-1/PD-L1 blockade therapies synergistically enhance the anti-tumor efficacy of PKCα inhibitors in breast cancer. [Display omitted]