mmune checkpoint inhibitors(ICIs),represented by anti-PD-1/PD-L1 antibodies,have been widely applied in various cancers,and the efficacy of ICIs is closely associated with the tumor immune microenvironment(TIME)[1,2]....mmune checkpoint inhibitors(ICIs),represented by anti-PD-1/PD-L1 antibodies,have been widely applied in various cancers,and the efficacy of ICIs is closely associated with the tumor immune microenvironment(TIME)[1,2].We previously demonstrated that the alveolar macrophage-derived chemokine CCL7 recruited conventional type 1 dendritic cells(cDC1s)to remodel the TIME,thereby promoting the expansion of T cells to inhibit non-small cell lung cancer(NSCLC)progression in KrasLSL-G12D/+Tp53fl/fl(KP)and KrasLSL-G12D/+Lkb1fl/fl(KL)mouse models[3].Here,we showed that the fusion protein PD-1Ab7,in which CCL7 was fused with the single-chain variable fragment region(scFv)of an anti-PD-1 antibody(PD-1Ab),exhibited antitumor activity superior to that of PD-1Ab in a manner dependent on cDC1s.In addition,Fms-like tyrosine kinase 3 ligand(Flt3L)synergized with PD-1Ab7 to inhibit NSCLC progression in both the KP and the KL mouse models.Mechanistically,Flt3L promoted the generation and proliferation of cDC1s,whereas PD-1Ab7 increased the infiltration and migration of cDC1s in the TIME to potentiate the activation and proliferation of T cells.These findings not only highlight the essential roles of the PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells to potentiate the efficacy of ICIs for cancer prevention but also provide therapeutic lead molecules for antitumor therapy.展开更多
Rabies is a zoonotic disease that still causes 59,000 human deaths each year,and rabies vaccine is the most effective way to control the disease.Our previous studies suggested that the maturation of DC plays an import...Rabies is a zoonotic disease that still causes 59,000 human deaths each year,and rabies vaccine is the most effective way to control the disease.Our previous studies suggested that the maturation of DC plays an important role in enhancing the immunogenicity of rabies vaccine.Flt3L has been reported to own the ability to accelerate the DC maturation,therefore,in this study,a recombinant rabies virus expressing mouse Flt3L,designated as LBNSE-Flt3L,was constructed,and its immunogenicity was characterized.It was found that LBNSE-FU3L could enhance the maturation of DC both in vitro and in vivo,and significantly more TFH cells and Germinal Center B(GC B)cells were generated in mice immunized with LBNSE-FU3L than those immunized with the parent virus LBNSE.Consequently,expressing of Flt3L could elevate the level of virus-neutralizing antibodies(VNA)in immunized mice which provides a better protection from a lethal rabies virus challenge.Taken together,our study extends the potential of Flt3L as a good adjuvant to develop novel rabies vaccine by enhancing the VNA production through activating the DC—Tfh^GC B axis in immunized mice.展开更多
Conventional dendritic cells(cDCs)scan and integrate environmental cues in almost every tissue,including exogenous metabolic signals.While cDCs are critical in maintaining immune balance,their role in preserving energ...Conventional dendritic cells(cDCs)scan and integrate environmental cues in almost every tissue,including exogenous metabolic signals.While cDCs are critical in maintaining immune balance,their role in preserving energy homeostasis is unclear.Here,we showed that Batf3-deficient mice lacking conventional type 1 DCs(cDC1s)had increased body weight and adiposity during aging.This led to impaired energy expenditure and glucose tolerance,insulin resistance,dyslipidemia,and liver steatosis.cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+invariant NKT(iNKT)cells.Accordingly,among antigen-presenting cells,cDC1s exhibited notable induction of IFN-γproduction by iNKT cells,which plays a metabolically protective role in lean adipose tissue.Flt3L treatment,which expands the dendritic cell(DC)compartment,mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner.This effect was partially mediated by NK1.1+cells.These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.展开更多
基金the National Key Research and Development Program of China(2022YFC3401500)the Natural Science Foundation of China(31930040,32070900,and32270951)the Fundamental Research Funds for the Central Universities(2042022kf1187).
文摘mmune checkpoint inhibitors(ICIs),represented by anti-PD-1/PD-L1 antibodies,have been widely applied in various cancers,and the efficacy of ICIs is closely associated with the tumor immune microenvironment(TIME)[1,2].We previously demonstrated that the alveolar macrophage-derived chemokine CCL7 recruited conventional type 1 dendritic cells(cDC1s)to remodel the TIME,thereby promoting the expansion of T cells to inhibit non-small cell lung cancer(NSCLC)progression in KrasLSL-G12D/+Tp53fl/fl(KP)and KrasLSL-G12D/+Lkb1fl/fl(KL)mouse models[3].Here,we showed that the fusion protein PD-1Ab7,in which CCL7 was fused with the single-chain variable fragment region(scFv)of an anti-PD-1 antibody(PD-1Ab),exhibited antitumor activity superior to that of PD-1Ab in a manner dependent on cDC1s.In addition,Fms-like tyrosine kinase 3 ligand(Flt3L)synergized with PD-1Ab7 to inhibit NSCLC progression in both the KP and the KL mouse models.Mechanistically,Flt3L promoted the generation and proliferation of cDC1s,whereas PD-1Ab7 increased the infiltration and migration of cDC1s in the TIME to potentiate the activation and proliferation of T cells.These findings not only highlight the essential roles of the PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells to potentiate the efficacy of ICIs for cancer prevention but also provide therapeutic lead molecules for antitumor therapy.
基金supported by the National Program on Key Research Project of China (2016YFD0500400 and 2017YFD0501701)the National Natural Science Foundation of China (31872494, 31402176, 31372419, and 31522057)+2 种基金the Fundamental Research Funds for the Central Universities (No. 2662016QD036 to MZ)the Ministry of Science and Technology of China (863 program, No. 2011AA10A212)the Ministry of Agriculture of China (Special Fund for Agro-scientific Research in the Public Interest, No. 201303042 to ZFF)
文摘Rabies is a zoonotic disease that still causes 59,000 human deaths each year,and rabies vaccine is the most effective way to control the disease.Our previous studies suggested that the maturation of DC plays an important role in enhancing the immunogenicity of rabies vaccine.Flt3L has been reported to own the ability to accelerate the DC maturation,therefore,in this study,a recombinant rabies virus expressing mouse Flt3L,designated as LBNSE-Flt3L,was constructed,and its immunogenicity was characterized.It was found that LBNSE-FU3L could enhance the maturation of DC both in vitro and in vivo,and significantly more TFH cells and Germinal Center B(GC B)cells were generated in mice immunized with LBNSE-FU3L than those immunized with the parent virus LBNSE.Consequently,expressing of Flt3L could elevate the level of virus-neutralizing antibodies(VNA)in immunized mice which provides a better protection from a lethal rabies virus challenge.Taken together,our study extends the potential of Flt3L as a good adjuvant to develop novel rabies vaccine by enhancing the VNA production through activating the DC—Tfh^GC B axis in immunized mice.
基金supported by the National Natural Science Foundation of China(No. 81470222)the Science and Technology Project of Chongqing(No. cstc2017jcyj B0160)the Science and Technology Project of Yuzhong District,Chongqing(No. 20170120)
基金Work in the S.I.laboratory is funded by the Spanish Ministerio de Ciencia,Innovación(MICINN),Agencia Estatal de Investigación(AEI)and Fondo Europeo de Desarrollo Regional(FEDER),RTI2018-094484-BI00,and RYC-2016-19463.EHG is the recipient of an FPI fellowship(PRE2019-087509)from the Spanish Ministry of Science and Innovation.Work in the DS laboratory is funded by the CNICthe European Research Council(ERC-2016-Consolidator Grant 725091)+4 种基金the MICINN,AEI and FEDER(PID2019-108157RB)Comunidad de Madrid(B2017/BMD-3733 Immunothercan-CM)Atresmedia(Constantes y Vitales prize)and FundacióLa Maratóde TV3(201723).Work in the G.S.laboratory receives funding from the European Union’s Seventh Framework Programme(FP7/2007-2013)under grant agreement n°ERC 260464,EFSD/Lilly European Diabetes Research Programme GS,2017 Leonardo Grant for Researchers and Cultural Creators,BBVA Foundation(Investigadores-BBVA-2017)IN[17]_BBM_BAS_0066,MINECO-FEDER SAF2016-79126-R,EUIN2017-85875,Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación AECC.IN receives funding from EFSD/Lilly(2019),EFSD Rising star(2019),and JdC-Incorporation(IJC2018-035390-I)The CNIC is supported by the Instituto de Salud Carlos III(ISCIII),the MICINN,and the Pro CNIC Foundation。
文摘Conventional dendritic cells(cDCs)scan and integrate environmental cues in almost every tissue,including exogenous metabolic signals.While cDCs are critical in maintaining immune balance,their role in preserving energy homeostasis is unclear.Here,we showed that Batf3-deficient mice lacking conventional type 1 DCs(cDC1s)had increased body weight and adiposity during aging.This led to impaired energy expenditure and glucose tolerance,insulin resistance,dyslipidemia,and liver steatosis.cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+invariant NKT(iNKT)cells.Accordingly,among antigen-presenting cells,cDC1s exhibited notable induction of IFN-γproduction by iNKT cells,which plays a metabolically protective role in lean adipose tissue.Flt3L treatment,which expands the dendritic cell(DC)compartment,mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner.This effect was partially mediated by NK1.1+cells.These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.
