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

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.
Cancer
Care/Management

Authors

Lopez-Janeiro Lopez-Janeiro, González-Gomariz González-Gomariz, Issa Issa, Hester Hester, Porciuncula Porciuncula, Teijeira Teijeira, Luri-Rey Luri-Rey, Ruiz-Guillamon Ruiz-Guillamon, Perez-Gracia Perez-Gracia, Perez-Ruiz Perez-Ruiz, Barragan Barragan, Martín-Algarra Martín-Algarra, Sanmamed Sanmamed, Ortego Ortego, Rodriguez-Ruiz Rodriguez-Ruiz, Alexandru Alexandru, Rodriguez Rodriguez, Arrieta-Aranzueque Arrieta-Aranzueque, Rimm Rimm, Aung Aung, Schalper Schalper, de Andrea de Andrea, Melero Melero
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