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

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外文摘要：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,respec-tively.The excessive TGF-β,secreted by tumor-infiltrated CCRl+-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-β through 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-β exhaustion 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-γ around tumors,thus eradicating metastatic foci.Our strategy elicits pleiotropic antimetastatic immunity,paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

外文关键词：

SMAD4-deficient CRCMetastasisG-MDSCsTGF-βCCR1TGFBR2Chemotactic nanovesiclesTertiary lymphoid structures

作者：

Boning Niu、Tianyi Tian、Lu Wang、Yinmei Tian、Tian Tian、Yuanyuan Guo、Hu Zhou、Zhiping Zhang

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作者单位：

Tongji School of Pharmacy,Huazhong University of Science and Technology,Wuhan 430030,China

Department of Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

Department of Pharmacy,Liyuan Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

School of Pharmaceutical Sciences,Fujian Provincial Key Laboratory of Innovative Drug Target Research,High Throughput Drug Screening Platform,Xiamen University,Xiamen 361102,China

National Engineering Research Center for Nanomedicine,Huazhong University of Science and Technology,Wuhan 430030,China

Hubei Engineering Research Centre for Novel Drug Delivery System,Huazhong University of Science and Technology,Wuhan 430030,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationProgram for HUST Academic Frontier Youth Team,China

项目编号：

82204309821034592021M7013272018QYTD13

出版年：

2024

DOI：

10.1016/j.apsb.2024.05.009

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(8)