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

• Published in: Cellular & molecular immunology Vol. 21; no. 4; pp. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2024; Nature Publishing Group
• Subjects: 631/250/21/1566; 631/250/2504/133; 631/250/580; Animal models; Antibodies; Antigen presentation; Biomedical and Life Sciences; Biomedicine; Cancer; CD4 antigen; CD40 antigen; CD8 antigen; Cytotoxicity; Dendritic cells; Immune checkpoint inhibitors; Immunology; Immunotherapy; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical Microbiology; Medical prognosis; Microbiology; PD-1 protein; Transcriptomics; Vaccine; β-Interferon; CTL priming; Tumor control; CD4+ T-cell help; cDC1 licensing; (cross-)presentation; IFN-I signaling; CD40 costimulation
• ISSN: 2042-0226; 1672-7681; 2042-0226
• DOI: 10.1038/s41423-024-01133-1

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.