Remolding the tumor microenvironment by bacteria augments adoptive T cell therapy in advanced-stage solid tumors  

作　　者：Chaojie Zhu Chao Liu Qing Wu Tao Sheng Ruyi Zhou En Ren Ruizhe Zhang Zhengjie Zhao Jiaqi Shi Xinyuan Shen Zhongquan Sun Zhengwei Mao Kaixin He Lingxiao Zhang Yuan Ding Zhen Gu Weilin Wang Hongjun Li 

机构地区：[1]Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital,School of Medicine,Zhejiang University,310009 Hangzhou,China [2]National Key Laboratory of Advanced Drug Delivery and Release Systems,College of Pharmaceutical Sciences,Zhejiang University,310058 Hangzhou,China [3]Liangzhu Laboratory,Zhejiang University Medical Center,311121 Hangzhou,China [4]State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research,School of Pharmaceutical Sciences,Xiamen University,361102 Xiamen,China [5]MOE Key Laboratory of Macromolecular Synthesis and Functionalization,Department of Polymer Science and Engineering,Zhejiang University,310027 Hangzhou,China [6]Interdisciplinary Nanoscience Center,Aarhus University,Aarhus C DK-8000,Denmark [7]Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province,310009 Hangzhou,China [8]ZJU-Pujian Research&Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease,310058 Hangzhou,China [9]Jinhua Institute of Zhejiang University,321299 Jinhua,China [10]Department of General Surgery,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,310016 Hangzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第12期5765-5776,共12页信号转导与靶向治疗(英文)

基　　金：supported by the National Key R&D Program of China(2021YFA0909900);the National Natural Science Foundation of China(52173142,52233013);the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(2024C03168);the Startup Package of Zhejiang University.

摘　　要：The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells.Here,we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment.Our study reveals that intratumor injection of E.coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5,together facilitating tumor infiltration of adoptively transferred T cells.The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy.This combinatorial therapy,consisting of E.coli adjuvant and adoptive T-cell therapy,effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors.Notably,this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination.This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors,including melanoma and hepatocellular carcinoma,by converging attacks from both inside and outside the tumor tissues.

关 键 词：ADOPTIVE TRANSFERRED solid 

分 类 号：R73[医药卫生—肿瘤]