Zhou Minglu, Luo Chaohui, Zhou Zhou, Li Lian, Huang Yuan
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
J Control Release. 2021 Jun 10;334:248-262. doi: 10.1016/j.jconrel.2021.04.029. Epub 2021 Apr 27.
Triple negative breast cancer (TNBC) with highly metastatic features generally does not respond to anti-programmed cell death 1 ligand 1 (PD-L1) therapy due to multiple immunosuppressive mechanisms to exclude and disable T cells. Here, we develop a polymer-based combinatory approach consisting of both immunogenic cell death (ICD)-inducing and CXCR4-inhibiting function to prime tumor microenvironment and improve anti-PD-L1 therapy in TNBC. Our findings revealed that the combination therapy was able to spur the T cell response in primary tumors by increasing the tumor immunogenicity to recruit T cells, removing the physiological barriers of intratumoral fibrosis and collagen to increase T cell infiltration, and reducing the immunosuppressive cells to revive T cells. Meanwhile, such approach efficiently inhibited the formation of pre-metastatic niche in abscopal lung. Because of the significant promotion of anti-tumor and anti-metastasis immunity, the non-responding TNBC gained robust responsiveness to anti-PD-L1 therapy which resulted in complete eradication of orthotopic tumors, inhibition of pulmonary metastasis, and durable memory effects against tumor recurrence. Our work provided a generalizable approach of simultaneous ICD induction and CXCR4 blockade to apply anti-PD-L1 therapy in TNBC.
具有高转移特征的三阴性乳腺癌（TNBC）通常对抗程序性细胞死亡蛋白1配体1（PD-L1）治疗无反应，这是由于存在多种免疫抑制机制来排除和使T细胞失活。在此，我们开发了一种基于聚合物的联合方法，该方法兼具诱导免疫原性细胞死亡（ICD）和抑制CXCR4的功能，以启动肿瘤微环境并改善TNBC中的抗PD-L1治疗。我们的研究结果表明，联合治疗能够通过提高肿瘤免疫原性以招募T细胞、消除肿瘤内纤维化和胶原蛋白的生理屏障以增加T细胞浸润以及减少免疫抑制细胞以恢复T细胞活性，从而刺激原发性肿瘤中的T细胞反应。同时，这种方法有效地抑制了远隔部位肺脏中前转移生态位的形成。由于显著促进了抗肿瘤和抗转移免疫，原本无反应的TNBC对抗PD-L1治疗产生了强大的反应性，从而导致原位肿瘤被完全根除、肺转移受到抑制，并对肿瘤复发产生持久的记忆效应。我们的工作提供了一种可推广的方法，即同时诱导ICD和阻断CXCR4，以在TNBC中应用抗PD-L1治疗。
