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
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.
