Choe Eun-Ji, Lee Chan-Hyeong, Bae Ju-Hyun, Park Ju-Mi, Park Seong-Sik, Baek Moon-Chang
Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu 41944, Korea.
Pharmaceutics. 2022 Aug 9;14(8):1660. doi: 10.3390/pharmaceutics14081660.
According to clinical studies, statins improve the efficacy of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade therapy for breast cancer; however, the underlying mechanisms are unclear. Herein, we showed that atorvastatin (ATO) decreased the content of PD-L1 in extracellular vesicles (EVs) by reducing cellular PD-L1 expression and inhibiting EV secretion in breast cancer cells, thereby enhancing the efficacy of anti-PD-L1 therapy. ATO reduced EV secretion by regulating the Rab proteins involved in EV biogenesis and secretion. ATO-mediated inhibition of the Ras-activated MAPK signaling pathway downregulated PD-L1 expression. In addition, ATO strongly promoted antitumor efficacy by inducing T cell-mediated tumor destruction when combined with an anti-PD-L1 antibody. Moreover, suppression of EV PD-L1 by ATO improved the reactivity of anti-PD-L1 therapy by enhancing T-cell activity in draining lymph nodes of EMT6-bearing immunocompetent mice. Therefore, ATO is a potential therapeutic drug that improves antitumor immunity by inhibiting EV PD-L1, particularly in response to immune escape during cancer.
根据临床研究，他汀类药物可提高程序性死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）阻断疗法对乳腺癌的疗效；然而，其潜在机制尚不清楚。在此，我们表明阿托伐他汀（ATO）通过降低细胞PD-L1表达和抑制乳腺癌细胞中细胞外囊泡（EVs）的分泌，降低了EVs中PD-L1的含量，从而增强了抗PD-L1疗法的疗效。ATO通过调节参与EV生物发生和分泌的Rab蛋白来减少EV分泌。ATO介导的对Ras激活的MAPK信号通路的抑制下调了PD-L1的表达。此外，当与抗PD-L1抗体联合使用时，ATO通过诱导T细胞介导的肿瘤破坏强烈促进抗肿瘤疗效。此外，ATO对EV PD-L1的抑制通过增强荷EMT6免疫活性小鼠引流淋巴结中的T细胞活性，提高了抗PD-L1疗法的反应性。因此，ATO是一种潜在的治疗药物，可通过抑制EV PD-L1来提高抗肿瘤免疫力，特别是在癌症免疫逃逸期间。
