YANG SUAH 심만규 송수경 Hanhee Cho choi, ji woong Seong Ik Jeon Kim W.J. Um W. Park J.H. 윤홍열 Kim, Kwang meyung 2024-01-12T02:35:42Z 2024-01-12T02:35:42Z 2022-11-03 2022-11 0142-9612 https://pubs.kist.re.kr/handle/201004/75951 Immune checkpoint blockade (ICB) has shown remarkable therapeutic efficacy in a variety of cancers. However, patients exhibit unexpectedly low response rates to ICB therapy owing to the unwanted recycling and cellular abundance of PD-L1. Herein, rational design of PD-L1 multivalent binding liposome is investigated through PEGylated liposomes incorporating different ratios of PD-L1 binding peptide. Liposomes incorporating 10 mol% PD-L1 binding peptides (10-PD-L1-Lipo) promote the multivalent binding with PD-L1 on tumor cell surface, which is endocytosed for its trafficking toward the lysosomes instead of the recycling endosomes. Thereby, 10-PD-L1-Lipo leads to a significant PD-L1 degradation that prevents its recycling and cellular abundance compared to anti-PD-L1 antibody, disrupting immune escape mechanism of tumor cells and enhancing T cell-mediated antitumor immunity. Moreover, a clinically applicable doxorubicin (DOX) liposomal formulation is established via drug encapsulation into 10-PD-L1-Lipo. The resulting DOX-PD-L1-Lipo primes tumors via immunogenic chemotherapy by preferential DOX accumulation by the EPR effect and overcomes PD-L1 abundance induced following chemotherapy through multivalent binding-mediated PD-L1 degradation. As a result, the synergistic immunogenic chemotherapy and multivalent binding-mediated PD-L1 degradation by DOX-PD-L1-Lipo show significantly enhanced antitumor efficacy and immune responses in colon tumor models. Collectively, this study suggests the rationally designed PEGylated liposomes to promote PD-L1 multivalent binding providing a new route for safe and more effective ICB therapy. English Pergamon Press Ltd. Liposome-mediated PD-L1 multivalent binding promotes the lysosomal degradation of PD-L1 for T cell-mediated antitumor immunity Article 10.1016/j.biomaterials.2022.121841 1 Biomaterials, v.290 Biomaterials 290 N scie scopus 000876551100001 2-s2.0-85139240012 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article DEATH CHECKPOINT BLOCKADE EXPRESSION CMTM6 Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Multivalent binding PD-L1 binding peptide