TY  - JOUR
AU  - Lei, Xin
AU  - Khatri, Indu
AU  - de Wit, Tom
AU  - de Rink, Iris
AU  - Nieuwland, Marja
AU  - Kerkhoven, Ron
AU  - van Eenennaam, Hans
AU  - Sun, Chong
AU  - Garg, Abhishek D
AU  - Borst, Jannie
AU  - Xiao, Yanling
TI  - CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-00114
SP  - 217
PY  - 2023
AB  - Despite their low abundance in the tumor microenvironment (TME), classical type 1 dendritic cells (cDC1) play a pivotal role in anti-cancer immunity, and their abundance positively correlates with patient survival. However, their interaction with CD4+ T-cells to potentially enable the cytotoxic T lymphocyte (CTL) response has not been elucidated. Here we show that contact with activated CD4+ T-cells enables human ex vivo cDC1, but no other DC types, to induce a CTL response to cell-associated tumor antigens. Single cell transcriptomics reveals that CD4+ T-cell help uniquely optimizes cDC1 in many functions that support antigen cross-presentation and T-cell priming, while these changes don't apply to other DC types. We robustly identify 'helped' cDC1 in the TME of a multitude of human cancer types by the overlap in their transcriptomic signature with that of recently defined, tumor-infiltrating DC states that prove to be positively prognostic. As predicted from the functional effects of CD4+ T-cell help, the transcriptomic signature of 'helped' cDC1 correlates with tumor infiltration by CTLs and Thelper(h)-1 cells, overall survival and response to PD-1-targeting immunotherapy. These findings reveal a critical role for CD4+ T-cell help in enabling cDC1 function in the TME and may establish the helped cDC1 transcriptomic signature as diagnostic marker in cancer.
KW  - Humans
KW  - CD8-Positive T-Lymphocytes
KW  - Neoplasms: metabolism
KW  - Antigen Presentation
KW  - T-Lymphocytes, Cytotoxic
KW  - Dendritic Cells
KW  - T-Lymphocytes, Helper-Inducer: metabolism
KW  - Tumor Microenvironment
LB  - PUB:(DE-HGF)16
C6  - pmid:36639382
C2  - pmc:PMC9839676
DO  - DOI:10.1038/s41467-022-35615-5
UR  - https://inrepo02.dkfz.de/record/210385
ER  -