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
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.
