Conventional type-1 DC density is associated with checkpoint inhibitor response across multiple types of cancer.

Lopez-Janeiro A., González-Gomariz J., Issa F., Hester J., Porciuncula A., Teijeira A., Luri-Rey C., Ruiz-Guillamon D., Perez-Gracia JL., Perez-Ruiz E., Barragan I., Martín-Algarra S., Sanmamed MF., Ortego I., Rodriguez-Ruiz ME., Alexandru R., Rodriguez I., Arrieta-Aranzueque S., Rimm D., Aung T., Schalper KA., de Andrea CE., Melero I.

Conventional type-1 dendritic cells (cDC1) are the main mediators of crosspresentation of tumor antigens to CD8+ T cells and provide a context of costimulatory molecules and cytokines that lead to cytotoxic T lymphocyte (CTL) responses. We analyzed bulk RNA sequences from 7 key clinical trials testing checkpoint inhibitors across multiple cancer types. cDC1- and CD8-associated gene signatures were analyzed. Multiplex tissue immunofluorescence was used to quantify cDC1 in melanoma, urothelial cancer, and non-small-cell lung cancer (NSCLC) samples and assess cDC1 tissue neighborhoods. Melanoma samples were studied with Xenium spatial transcriptomics (ST) and one series of NSCLC was analyzed using GeoMX-DSP. Strong associations across tumor types were found between cDC1 and CD8+ T cell transcripts with clinical outcomes. As mechanistically expected, transcripts for the CCL4 and CCL5 chemokines and the growth factor FLT3-L showed associations with cDC1 abundance. Tissue immunofluorescence showed a strong correlation of cDC1 and CD8+ T cell infiltration with clinical benefit upon treatment with checkpoint inhibitors (CPIs). Moreover, short distance between cDC1 and CD8+ T cells was found to define tissue niches associated with favorable outcomes. ST revealed recent T cell activation within immune cDC1-rich niches. cDC1 abundance, which determines CD8+ T lymphocyte density and activation in tumor tissues across cancer types, is strongly associated with clinical response to CPI-based immunotherapies.

DOI

10.1172/JCI200987

Type

Journal article

Publication Date

2026-05-01T00:00:00+00:00

Volume

136

Keywords

Cancer immunotherapy, Dendritic cells, Immunology, Oncology, Humans, Immune Checkpoint Inhibitors, Dendritic Cells, CD8-Positive T-Lymphocytes, Neoplasms, Female, Male

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