Liposome-mediated PD-L1 multivalent binding promotes the lysosomal degradation of PD-L1 for T cell-mediated antitumor immunity

Authors
YANG SUAH심만규송수경Hanhee Chochoi, ji woongSeong Ik JeonKim W.J.Um W.Park J.H.윤홍열Kim, Kwang meyung
Issue Date
2022-11
Publisher
Pergamon Press Ltd.
Citation
Biomaterials, v.290
Abstract
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.
Keywords
DEATH; CHECKPOINT BLOCKADE; EXPRESSION; CMTM6; Cancer immunotherapy; Immune checkpoint blockade; PEGylated liposome; Multivalent binding; PD-L1 binding peptide
ISSN
0142-9612
URI
https://pubs.kist.re.kr/handle/201004/75951
DOI
10.1016/j.biomaterials.2022.121841
Appears in Collections:
KIST Article > 2022
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