Background Chronic obstructive pulmonary disease （COPD） is a progressive disease associated with a cellular inflammatory response mostly concerned with cigarette smoking. Chemokine receptors CCRI/5 play an important...Background Chronic obstructive pulmonary disease （COPD） is a progressive disease associated with a cellular inflammatory response mostly concerned with cigarette smoking. Chemokine receptors CCRI/5 play an important role in the inflammatory cells recruitment in the lung of COPD patients. The aim of this study was to determine the impact of cigarette smoking on the expression of CCRI/5 on inflammatory cells in induced sputum, and the relationship between the receptors expression and COPD severity. Methods Differential cells in induced sputum were counted and the optical densities of CCR1 and CCR5 on inflammatory cells in induced sputum from COPD patients （n=29）, healthy smokers （n=11）, and nonsmokers （n=6） were measured using immunocytochemistry. Concentrations of CCL3, the ligand of CCRI/5, in supernatant of induced sputum were detected by enzyme-linked immunosorbent assay. Results The expressions of CCR1 and CCR5 on inflammatory cells in healthy smokers were significantly higher than those in nonsmokers, and the expression of CCR1 in patients with COPD was significantly increased when compared with nonsmokers but not healthy smokers. The expressions of CCR1 and CCR5 on inflammatory cells in severe and very severe COPD patients were higher compared with mild and moderate COPD patients. CCL3 level was positively correlated with the total cell counts in induced sputum and smoking history, and negatively correlated with percentage of predicted FEV1. Conclusions Cigarette smoking could increase the expression of CCR1 on the inflammatory cells. Both CCR1 and CCR5 expressions on the inflammatory cells in induced sputum could be associated with COPD severity.展开更多
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
基金This work was supported by grants from the National Natural Science Foundation of China （No. 30370608） and the Ph.D. Programs Foundation of Ministry of Education of China （No. 20050001143）.
文摘Background Chronic obstructive pulmonary disease （COPD） is a progressive disease associated with a cellular inflammatory response mostly concerned with cigarette smoking. Chemokine receptors CCRI/5 play an important role in the inflammatory cells recruitment in the lung of COPD patients. The aim of this study was to determine the impact of cigarette smoking on the expression of CCRI/5 on inflammatory cells in induced sputum, and the relationship between the receptors expression and COPD severity. Methods Differential cells in induced sputum were counted and the optical densities of CCR1 and CCR5 on inflammatory cells in induced sputum from COPD patients （n=29）, healthy smokers （n=11）, and nonsmokers （n=6） were measured using immunocytochemistry. Concentrations of CCL3, the ligand of CCRI/5, in supernatant of induced sputum were detected by enzyme-linked immunosorbent assay. Results The expressions of CCR1 and CCR5 on inflammatory cells in healthy smokers were significantly higher than those in nonsmokers, and the expression of CCR1 in patients with COPD was significantly increased when compared with nonsmokers but not healthy smokers. The expressions of CCR1 and CCR5 on inflammatory cells in severe and very severe COPD patients were higher compared with mild and moderate COPD patients. CCL3 level was positively correlated with the total cell counts in induced sputum and smoking history, and negatively correlated with percentage of predicted FEV1. Conclusions Cigarette smoking could increase the expression of CCR1 on the inflammatory cells. Both CCR1 and CCR5 expressions on the inflammatory cells in induced sputum could be associated with COPD severity.
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 the National Natural Science Foundation of China(82130004,81830007,and 82270194)the National Key Research and Development Program of China(2022YFC2502600)+7 种基金the Chang Jiang Scholars Program,the Shanghai Rising-Star Program(23QA1406100)the Shanghai Municipal Commission of Science and Technology Project(23141903100)the Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(20152206,20152208,and 20161303)the Clinical Research Plan of Shanghai Hospital Development Center(SHDC 2020CR1032B)the Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine(DLY201601)the Multi-center Hematology-Oncology Protocols Evaluation System(M-HOPES)network from Chinathe Samuel Waxman Cancer Research Foundationthe Center for High Performance Computing at Shanghai Jiao Tong University。
