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...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.展开更多
Background:EBV-miR-BARTs exhibit significant relevance in epithelial tumors,particularly in EBVassociated gastric and nasopharyngeal cancers.However,their specific mechanisms in the initiation and progression of gastr...Background:EBV-miR-BARTs exhibit significant relevance in epithelial tumors,particularly in EBVassociated gastric and nasopharyngeal cancers.However,their specific mechanisms in the initiation and progression of gastric cancer remain insufficiently explored.Material and Methods:Initially,EBV-miRNA-BART6-5p and its target gene SMAD4 expression were assessed in EBV-associated gastric cancer tissues and cell lines.Subsequent transfection induced overexpression of EBV-miRNA-BART6-5p in AGS and MKN-45,and downregulation in EBVpositive cells(SUN-719).The subsequent evaluation aimed to observe their impact on gastric cancer cell proliferation,migration,and glycolytic processes,with the TGF-β/SMAD4 signaling pathway value clarified using a TGF-βinhibitor.Results:EBV-miRNA-BART6-5p exhibits pronounced upregulation in EBV-associated gastric cancer tissues and EBV-positive cells,while its target gene SMAD4 demonstrates downregulated expression.Upregulation of it can promote the proliferation and migration of gastric cancer cells.Additionally,We found EBV-miRNA-BART6-5p promotes glycolysis of gastric cancer cells.Inhibition of the TGF-β/SMAD4 signaling pathway resulted in suppressed proliferation and migration of gastric cancer cells,concomitant with a diminished glycolytic capacity.Conclusion:In this study,we found that EBV-miRNA-BART6-5p can target SMAD4,effectively increasing glycolysis in gastric cancer cells by regulating the TGF-β/SMAD4 signaling pathway,thereby enhancing the proliferation and metastasis of gastric cancer cells.Our findings may offer new insights into the metabolic aspects of gastric cancer.展开更多
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).
文摘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.
基金supported by National Health Commission Key Laboratory of Gastrointestinal Tumour Diagnosis and Treatment 2022 Master/Postdoctoral Fund Project(NHCDP2022005)Gansu Provincial Science and Technology Department Joint Scientific Research Fund Project(23JRRA1545)+1 种基金Gansu Provincial Hospital Intra-Hospital Research Fund Project(22GSYYD-37)International Co-Operation Project of Gansu Provincial Science and Technology Department(No.20YF8WA096).
文摘Background:EBV-miR-BARTs exhibit significant relevance in epithelial tumors,particularly in EBVassociated gastric and nasopharyngeal cancers.However,their specific mechanisms in the initiation and progression of gastric cancer remain insufficiently explored.Material and Methods:Initially,EBV-miRNA-BART6-5p and its target gene SMAD4 expression were assessed in EBV-associated gastric cancer tissues and cell lines.Subsequent transfection induced overexpression of EBV-miRNA-BART6-5p in AGS and MKN-45,and downregulation in EBVpositive cells(SUN-719).The subsequent evaluation aimed to observe their impact on gastric cancer cell proliferation,migration,and glycolytic processes,with the TGF-β/SMAD4 signaling pathway value clarified using a TGF-βinhibitor.Results:EBV-miRNA-BART6-5p exhibits pronounced upregulation in EBV-associated gastric cancer tissues and EBV-positive cells,while its target gene SMAD4 demonstrates downregulated expression.Upregulation of it can promote the proliferation and migration of gastric cancer cells.Additionally,We found EBV-miRNA-BART6-5p promotes glycolysis of gastric cancer cells.Inhibition of the TGF-β/SMAD4 signaling pathway resulted in suppressed proliferation and migration of gastric cancer cells,concomitant with a diminished glycolytic capacity.Conclusion:In this study,we found that EBV-miRNA-BART6-5p can target SMAD4,effectively increasing glycolysis in gastric cancer cells by regulating the TGF-β/SMAD4 signaling pathway,thereby enhancing the proliferation and metastasis of gastric cancer cells.Our findings may offer new insights into the metabolic aspects of gastric cancer.
