Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membranedecorated nanoparticles  

作　　者：Wen Zhang Yihui Zhai Ying Cai Xiang Gong Yunxuan Jiang Rong Rong Chao Zheng Binyu Zhu Helen He Zhu Hao Wang Yaping Li Pengcheng Zhang 

机构地区：[1]China State Institute of Pharmaceutical Industry,Shanghai 201203,China [2]State Key Laboratory of Drug Research&Center of Pharmaceutics,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]School of Biomedical Engineering&State Key Laboratory of Advanced Medical Materials and Devices,ShanghaiTech University,Shanghai 201210,China [4]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China [5]Yantai Institute of Materia Medica,Shandong 264000,China [6]State Key Laboratory of Oncogenes and Related Genes,Renji-Med-X Stem Cell Research Center,Department of Urology,Ren Ji Hospital,School of Medicine and School of Biomedical Engineering,Shanghai Jiao Tong University,Shanghai 200127,China [7]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期3218-3231,共14页药学学报（英文版）

基　　金：financially supported by the National Natural Science Foundation of China(32371457,32171374 and 32130058);Shandong Laboratory Program(SYS202205,China).

摘　　要：Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocompatibility complex I(MHC-I)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with triple-negative breast cancer(TNBC).Here,we create a LCL161-loaded macrophage membrane decorated nanoparticle(LMN)for immunotherapy of MHC-I-deficient TNBC.SIRPa on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161,which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells.The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds.LMNs also block CD47-mediated phagocytosis suppression.LMNs inhibit the growth of MHC-I-deficient TNBC tumors,as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel,and prolong the survival of animals,during which process CTLs also play important roles.This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophagemediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.

关 键 词：MHC-I deficiency MACROPHAGE CD47 IMMUNOTHERAPY Triple-negative breast cancer PHAGOCYTOSIS Immune checkpoint Innate immunity 

分 类 号：R730.51[医药卫生—肿瘤]