CD4 + T cells produce IFN-I to license cDC1s for induction of cytotoxic T-cell activity in human tumors

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-infilt...

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Bibliographic Details
Published in:Cellular & molecular immunology 2024-04, Vol.21 (4), p.374-392
Main Authors: Lei, Xin, de Groot, Daniël C, Welters, Marij J P, de Wit, Tom, Schrama, Ellen, van Eenennaam, Hans, Santegoets, Saskia J, Oosenbrug, Timo, van der Veen, Annemarthe, Vos, Joris L, Zuur, Charlotte L, de Miranda, Noel F C C, Jacobs, Heinz, van der Burg, Sjoerd H, Borst, Jannie, Xiao, Yanling
Format: Article
Language:English
Subjects:
Animal models
Animals
Antigen presentation
Cancer
CD4 antigen
CD4-Positive T-Lymphocytes
CD40 antigen
CD8 antigen
CD8-Positive T-Lymphocytes
Cytotoxicity
Dendritic Cells
Humans
Immune checkpoint inhibitors
Immunotherapy
Lymphocytes
Lymphocytes T
Major histocompatibility complex
Medical prognosis
Mice
Neoplasms
PD-1 protein
Programmed Cell Death 1 Receptor - metabolism
T-Lymphocytes, Cytotoxic
Transcriptomics
β-Interferon
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Summary: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.
ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-024-01133-1