CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-β  

作　　者：Boning Niu Tianyi Tian Lu Wang Yinmei Tian Tian Tian Yuanyuan Guo Hu Zhou Zhiping Zhang 

机构地区：[1]Tongji School of Pharmacy,Huazhong University of Science and Technology,Wuhan 430030,China [2]Department of Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [3]Department of Pharmacy,Liyuan Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [4]School of Pharmaceutical Sciences,Fujian Provincial Key Laboratory of Innovative Drug Target Research,High Throughput Drug Screening Platform,Xiamen University,Xiamen 361102,China [5]National Engineering Research Center for Nanomedicine,Huazhong University of Science and Technology,Wuhan 430030,China [6]Hubei Engineering Research Centre for Novel Drug Delivery System,Huazhong University of Science and Technology,Wuhan 430030,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3711-3729,共19页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China(Nos.82204309,82103459);China Postdoctoral Science Foundation(No.2021M701327);the Program for HUST Academic Frontier Youth Team(No.2018QYTD13,China).

摘　　要：SMAD4 deficiency in colorectal cancer(CRC)is highly correlated with liver metastasis and high mortality,yet there are few effective precision therapies available.Here,we show that CCR1^(+)-granulocytic myeloid-derived suppressor cells(G-MDSCs)are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models,respectively.The excessive TGF-β,secreted by tumor-infiltrated CCR1^(+)-G-MDSCs,suppresses the immune response of cytotoxic T lymphocytes(CTLs),thus facilitating metastasis.Hereby,we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules(C/T-NVs)to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-βthrough TGF-β-TGFBR2 specific binding.Chemotactic C/T-NVs counteract CCR1^(+)-G-MDSC infiltration through competitive responding CCL9/CCR1 axis.C/T-NVs-induced intratumoral TGF-βexhaustion alleviates the TGF-β-suppressed immune response of CTLs.Collectively,C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC.In further exploration,high expression of programmed cell death ligand-1(PD-L1)is observed in clinical specimens of SMAD4-deficient CRC.Combining C/T-NVs with anti-PD-L1 antibody(aPD-L1)induces tertiary lymphoid structure formation with sustained activation of CTLs,CXCL13^(+)-CD4^(+)T,CXCR5^(+)-CD20^(+)B cells,and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γaround tumors,thus eradicating metastatic foci.Our strategy elicits pleiotropic antimetastatic immunity,paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

关 键 词：SMAD4-deficient CRC METASTASIS G-MDSCs TGF-Β CCR1 TGFBR2 

分 类 号：R730.5[医药卫生—肿瘤]