TY - JOUR
T1 - CD4+ T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors
AU - Lei, Xin
AU - de Groot, Daniël C.
AU - Welters, Marij J. P.
AU - de Wit, Tom
AU - Schrama, Ellen
AU - van Eenennaam, Hans
AU - Santegoets, Saskia J.
AU - Oosenbrug, Timo
AU - van der Veen, Annemarthe
AU - Vos, Joris L.
AU - Zuur, Charlotte L.
AU - de Miranda, Noel F. C. C.
AU - Jacobs, Heinz
AU - van der Burg, Sjoerd H.
AU - Borst, Jannie
AU - Xiao, Yanling
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024/4/1
Y1 - 2024/4/1
N2 - 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 IFNβ via 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), IFNβ also 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.
AB - 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 IFNβ via 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), IFNβ also 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.
KW - (cross-)presentation
KW - CD4+ T-cell help
KW - CD40 costimulation
KW - CTL priming
KW - IFN-I signaling
KW - Tumor control
KW - cDC1 licensing
UR - http://www.scopus.com/inward/record.url?scp=85185471160&partnerID=8YFLogxK
U2 - 10.1038/s41423-024-01133-1
DO - 10.1038/s41423-024-01133-1
M3 - Article
C2 - 38383773
SN - 1672-7681
VL - 21
SP - 374
EP - 392
JO - Cellular & molecular immunology
JF - Cellular & molecular immunology
IS - 4
ER -