CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s...CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.展开更多
Recombinant interleukin-33(IL-33)inhibits tumor growth,but the detailed immunological mechanism is still unknown.IL-33-mediated tumor suppression did not occur in Batf3^(−/−)mice,indicating that conventional type 1 de...Recombinant interleukin-33(IL-33)inhibits tumor growth,but the detailed immunological mechanism is still unknown.IL-33-mediated tumor suppression did not occur in Batf3^(−/−)mice,indicating that conventional type 1 dendritic cells(cDC1s)play a key role in IL-33-mediated antitumor immunity.A population of CD103^(+)cDC1s,which were barely detectable in the spleens of normal mice,increased significantly in the spleens of IL-33-treated mice.The newly emerged splenic CD103^(+)cDC1s were distinct from conventional splenic cDC1s based on their spleen residency,robust effector T-cell priming ability,and surface expression of FCGR3.DCs and DC precursors did not express Suppressor of Tumorigenicity 2(ST2).However,recombinant IL-33 induced spleen-resident FCGR3^(+)CD103^(+)cDC1s,which were found to be differentiated from DC precursors by bystander ST2+immune cells.Through immune cell fractionation and depletion assays,we found that IL-33-primed ST2^(+)basophils play a crucial role in the development of FCGR3^(+)CD103^(+)cDC1s by secreting IL-33-driven extrinsic factors.Recombinant GM-CSF also induced the population of CD103^(+)cDC1s,but the population neither expressed FCGR3 nor induced any discernable antitumor immunity.The population of FCGR3^(+)CD103^(+)cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs(FL-BMDCs)when IL-33 was added in a pre-DC stage of culture.FL-BMDCs generated in the presence of IL-33(FL-33-DCs)offered more potent tumor immunotherapy than control Flt3L-BMDCs(FL-DCs).Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors.Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.展开更多
This research investigates the regulatory role of the transcription factor PU.1 in type 1 conventional dendritic cells(cDC1)and its therapeutic potential of modulating the nuclear factor kappaB(NF-κB)cells signaling ...This research investigates the regulatory role of the transcription factor PU.1 in type 1 conventional dendritic cells(cDC1)and its therapeutic potential of modulating the nuclear factor kappaB(NF-κB)cells signaling pathway in non-small cell lung cancer(NSCLC).Utilizing single-cell transcriptome sequencing and comprehensive bioinformatics tools,including the CIBERSORT algorithm,we analyzed the immune cell landscape within NSCLC tissues.Our analysis revealed distinct NSCLC subtypes and delineated the developmental trajectories and functional distinctions of cDC1 cells.Key differentially expressed genes(DEGs)and pivotal functional modules within these cells were identified,highlighting PU.1 as a critical mediator underexpressed in NSCLC samples.Functionally,PU.1 demonstrated the induction of the NF-κB pathway,which led to inhibited tumor proliferation and enhanced activation of cDC1,thereby suggesting its role in tumor immune surveillance.In vivo models confirmed the suppressive effect of PU.1 on NSCLC progression,mediated through its influence on cDC1 functionality via the NF-κB pathway.These findings propose PU.1 as a promising target for NSCLC therapeutic strategies,emphasizing the importance of transcriptional regulators in the tumor microenvironment.展开更多
文摘CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.
基金the National Research Foundation of Korea(SRC-2017R1A5A1014560). This work was supported by grants from the National Research Foundation of Korea(SRC-2017R1A5A1014560)。
文摘Recombinant interleukin-33(IL-33)inhibits tumor growth,but the detailed immunological mechanism is still unknown.IL-33-mediated tumor suppression did not occur in Batf3^(−/−)mice,indicating that conventional type 1 dendritic cells(cDC1s)play a key role in IL-33-mediated antitumor immunity.A population of CD103^(+)cDC1s,which were barely detectable in the spleens of normal mice,increased significantly in the spleens of IL-33-treated mice.The newly emerged splenic CD103^(+)cDC1s were distinct from conventional splenic cDC1s based on their spleen residency,robust effector T-cell priming ability,and surface expression of FCGR3.DCs and DC precursors did not express Suppressor of Tumorigenicity 2(ST2).However,recombinant IL-33 induced spleen-resident FCGR3^(+)CD103^(+)cDC1s,which were found to be differentiated from DC precursors by bystander ST2+immune cells.Through immune cell fractionation and depletion assays,we found that IL-33-primed ST2^(+)basophils play a crucial role in the development of FCGR3^(+)CD103^(+)cDC1s by secreting IL-33-driven extrinsic factors.Recombinant GM-CSF also induced the population of CD103^(+)cDC1s,but the population neither expressed FCGR3 nor induced any discernable antitumor immunity.The population of FCGR3^(+)CD103^(+)cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs(FL-BMDCs)when IL-33 was added in a pre-DC stage of culture.FL-BMDCs generated in the presence of IL-33(FL-33-DCs)offered more potent tumor immunotherapy than control Flt3L-BMDCs(FL-DCs).Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors.Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.
文摘This research investigates the regulatory role of the transcription factor PU.1 in type 1 conventional dendritic cells(cDC1)and its therapeutic potential of modulating the nuclear factor kappaB(NF-κB)cells signaling pathway in non-small cell lung cancer(NSCLC).Utilizing single-cell transcriptome sequencing and comprehensive bioinformatics tools,including the CIBERSORT algorithm,we analyzed the immune cell landscape within NSCLC tissues.Our analysis revealed distinct NSCLC subtypes and delineated the developmental trajectories and functional distinctions of cDC1 cells.Key differentially expressed genes(DEGs)and pivotal functional modules within these cells were identified,highlighting PU.1 as a critical mediator underexpressed in NSCLC samples.Functionally,PU.1 demonstrated the induction of the NF-κB pathway,which led to inhibited tumor proliferation and enhanced activation of cDC1,thereby suggesting its role in tumor immune surveillance.In vivo models confirmed the suppressive effect of PU.1 on NSCLC progression,mediated through its influence on cDC1 functionality via the NF-κB pathway.These findings propose PU.1 as a promising target for NSCLC therapeutic strategies,emphasizing the importance of transcriptional regulators in the tumor microenvironment.
