Susceptibility to pathogens in the elderly is heightened with age,largely because of immunosenescence.As an immune regulatory organ,bone marrow creates immune cells that move to other organs and tis-sues through the b...Susceptibility to pathogens in the elderly is heightened with age,largely because of immunosenescence.As an immune regulatory organ,bone marrow creates immune cells that move to other organs and tis-sues through the blood.Despite the significance of this process of this organ,there is limited research on changes in immune cell generation in the bone marrow and their effects on immunosenescence.In this study,the compositions of immune cells in bone marrow from young(three months)and old(24+months)mice were compared by means of mass cytometry,with further validation obtained through the reanalysis of single-cell RNA sequencing data and cell sorting via flow cytometry.The effects of differential immune cells on immunosenescence in old mice were evaluated using the Clostridium difficile(C.difficile)infection model.Our results showed that aged mice presented with a reduction in bone tra-beculae structure,which was accompanied by a notable increase in polymorphonuclear(PMN)-myeloid-derived suppressor cell(MDSC)abundance.Through bulk-seq and reverse transcription quantitative polymerase chain reaction(RT-qPCR)analysis,we identified differential genes associated with the immune response—specifically,the Th17 cell differentiation pathway.Furthermore,the increase in exported PMN-MDSCs to the large intestine resulted in increased gut permeability and inflammatory damage to the colon following C.difficile infection.After clearing the PMN-MDSCs in old mice using the anti-Gr-1 antibody,the symptoms induced by C.difficile were significantly relieved,as evidenced by an inhibited IL-17 pathway in the colon and reduced gut permeability.In conclusion,aging increases the number of PMN-MDSCs in both the generated bone marrow and the outputted intestine,which con-tributes to susceptibility to C.difficile infection.This study provides a novel target for anti-aging therapy for immunosenescence,which is beneficial for improving immune function in elders.展开更多
Recruitment of polymorphonuclear MDSCs(PMN-MDSCs)in the TME suppresses the antitumor activity of tumor-infiltrating CD8^(+)T cells(CD8^(+)TILs).Little is known about the role of antitumoral CD8^(+)TILs in actively ini...Recruitment of polymorphonuclear MDSCs(PMN-MDSCs)in the TME suppresses the antitumor activity of tumor-infiltrating CD8^(+)T cells(CD8^(+)TILs).Little is known about the role of antitumoral CD8^(+)TILs in actively initiating an immune-tolerant microenvironment,particularly in the recruitment of PMN-MDSCs.In this study,we found that immunotherapy-activated CD8^(+)TILs significantly increased PNM-MDSC infltration in the TME,resulting in antitumor resistance.When CD8^(+)T cells are activated,lipocalin-2(LCN2)expression is strongly upregulated,which significantly enhances PMN-MDSC chemotaxis.Mechanistically,immune activation increased fatty acid synthesis in CD8T cells,particularly oleic acid(OA),which induced lysosomal membrane permeabilization,releasing cathepsin B and subsequently activating NF-kB to promote LCN2 expression.Moreover,we showed that glucagon-like peptide 1(GLP1)effectively inhibited OA synthesis in activated CD8^(+)T cells,reducing LCN2 production.We then developed a recombinant adenovirus encoding GLP1(AdV-GLP1),which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8^(+)TILs.In various pancreatic cancer models,including subcutaneous,orthotopic,and humanized CDX/PDX models,AdV-GLP1 displayed excellent antitumor efficacy.Our work advances the understanding of how immunotherapy-activated CD8^(+)TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improvecancer immunotherapy.展开更多
Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity.N-acetyl-aspartyl-glutamate(NAAG)has been extensively studied in neurological disorders;however,its potential role ...Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity.N-acetyl-aspartyl-glutamate(NAAG)has been extensively studied in neurological disorders;however,its potential role in restricting anti-tumor immunity has not been investigated.Here,we demonstrated that NAAG or its synthetase RimK-like family member B(RIMKLB)significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs),which in turn promoted breast cancer growth and metastasis.Mechanistically,NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor(NR2B-NMDAR)-dependent p38-NOTCH1 axis,and subsequently stimulating tumor cell migration and invasion,as well as inducing PMN-MDSC differentiation and expansion.In mouse models,RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression.An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients.Collectively,our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.展开更多
基金supported by the National Key Research and Development Program of China(2022YFF1100504)the 111 project from the Education Ministry of China(B18053)+2 种基金the National Natural Science Foundation of China(32101938 and 32302758)the China Postdoctoral Science Foundation(2022M723422)the Postdoctoral Fellowship Program of CPSF(GZB20230848).
文摘Susceptibility to pathogens in the elderly is heightened with age,largely because of immunosenescence.As an immune regulatory organ,bone marrow creates immune cells that move to other organs and tis-sues through the blood.Despite the significance of this process of this organ,there is limited research on changes in immune cell generation in the bone marrow and their effects on immunosenescence.In this study,the compositions of immune cells in bone marrow from young(three months)and old(24+months)mice were compared by means of mass cytometry,with further validation obtained through the reanalysis of single-cell RNA sequencing data and cell sorting via flow cytometry.The effects of differential immune cells on immunosenescence in old mice were evaluated using the Clostridium difficile(C.difficile)infection model.Our results showed that aged mice presented with a reduction in bone tra-beculae structure,which was accompanied by a notable increase in polymorphonuclear(PMN)-myeloid-derived suppressor cell(MDSC)abundance.Through bulk-seq and reverse transcription quantitative polymerase chain reaction(RT-qPCR)analysis,we identified differential genes associated with the immune response—specifically,the Th17 cell differentiation pathway.Furthermore,the increase in exported PMN-MDSCs to the large intestine resulted in increased gut permeability and inflammatory damage to the colon following C.difficile infection.After clearing the PMN-MDSCs in old mice using the anti-Gr-1 antibody,the symptoms induced by C.difficile were significantly relieved,as evidenced by an inhibited IL-17 pathway in the colon and reduced gut permeability.In conclusion,aging increases the number of PMN-MDSCs in both the generated bone marrow and the outputted intestine,which con-tributes to susceptibility to C.difficile infection.This study provides a novel target for anti-aging therapy for immunosenescence,which is beneficial for improving immune function in elders.
基金supported by the National Natural Science Foundation of China(82273261 to JW,82073367 to MX),Nanjing University(0214/151130 to JW)the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University(ZzYJ-202401 to JW).
文摘Recruitment of polymorphonuclear MDSCs(PMN-MDSCs)in the TME suppresses the antitumor activity of tumor-infiltrating CD8^(+)T cells(CD8^(+)TILs).Little is known about the role of antitumoral CD8^(+)TILs in actively initiating an immune-tolerant microenvironment,particularly in the recruitment of PMN-MDSCs.In this study,we found that immunotherapy-activated CD8^(+)TILs significantly increased PNM-MDSC infltration in the TME,resulting in antitumor resistance.When CD8^(+)T cells are activated,lipocalin-2(LCN2)expression is strongly upregulated,which significantly enhances PMN-MDSC chemotaxis.Mechanistically,immune activation increased fatty acid synthesis in CD8T cells,particularly oleic acid(OA),which induced lysosomal membrane permeabilization,releasing cathepsin B and subsequently activating NF-kB to promote LCN2 expression.Moreover,we showed that glucagon-like peptide 1(GLP1)effectively inhibited OA synthesis in activated CD8^(+)T cells,reducing LCN2 production.We then developed a recombinant adenovirus encoding GLP1(AdV-GLP1),which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8^(+)TILs.In various pancreatic cancer models,including subcutaneous,orthotopic,and humanized CDX/PDX models,AdV-GLP1 displayed excellent antitumor efficacy.Our work advances the understanding of how immunotherapy-activated CD8^(+)TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improvecancer immunotherapy.
基金supported by the National Key Research and Development Program of China(2023YFC2506400 and 2020YFA0112300)the National Natural Science Foundation of China(82230103,82073267,W2431054,81930075,and 82372689)+2 种基金“Ten Thousand Plan”-National High-Level Talents Special Support Plan(WR-YK5202101)Program for Outstanding Leading Talents in Shanghai,Program for Outstanding Medical Academic Leader in Shanghai(2019LJ04)Program of Shanghai Academic/Technology Research Leader(20XD1400700)。
文摘Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity.N-acetyl-aspartyl-glutamate(NAAG)has been extensively studied in neurological disorders;however,its potential role in restricting anti-tumor immunity has not been investigated.Here,we demonstrated that NAAG or its synthetase RimK-like family member B(RIMKLB)significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs),which in turn promoted breast cancer growth and metastasis.Mechanistically,NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor(NR2B-NMDAR)-dependent p38-NOTCH1 axis,and subsequently stimulating tumor cell migration and invasion,as well as inducing PMN-MDSC differentiation and expansion.In mouse models,RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression.An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients.Collectively,our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.
