Conventional type-1 DC density is associated with checkpoint inhibitor response across multiple types of cancer
Alvaro Lopez-Janeiro, José González-Gomariz, Fadi Issa, Joanna Hester, Angelo Porciuncula, Alvaro Teijeira, Carlos Luri-Rey, David Ruiz-Guillamon, Jose Luis Perez-Gracia, Elisabeth Perez-Ruiz, Isabel Barragan, Salvador Martín-Algarra, Miguel F. Sanmamed, Ignacio Ortego, Maria E. Rodriguez-Ruiz, Raluca Alexandru, Inmaculada Rodriguez, Saioa Arrieta-Aranzueque, David Rimm, Thazin Aung, Kurt A. Schalper, Carlos E. de Andrea, Ignacio Melero
Alvaro Lopez-Janeiro, José González-Gomariz, Fadi Issa, Joanna Hester, Angelo Porciuncula, Alvaro Teijeira, Carlos Luri-Rey, David Ruiz-Guillamon, Jose Luis Perez-Gracia, Elisabeth Perez-Ruiz, Isabel Barragan, Salvador Martín-Algarra, Miguel F. Sanmamed, Ignacio Ortego, Maria E. Rodriguez-Ruiz, Raluca Alexandru, Inmaculada Rodriguez, Saioa Arrieta-Aranzueque, David Rimm, Thazin Aung, Kurt A. Schalper, Carlos E. de Andrea, Ignacio Melero
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Research Article Immunology Oncology

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

Abstract

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.

Authors

Alvaro Lopez-Janeiro, José González-Gomariz, Fadi Issa, Joanna Hester, Angelo Porciuncula, Alvaro Teijeira, Carlos Luri-Rey, David Ruiz-Guillamon, Jose Luis Perez-Gracia, Elisabeth Perez-Ruiz, Isabel Barragan, Salvador Martín-Algarra, Miguel F. Sanmamed, Ignacio Ortego, Maria E. Rodriguez-Ruiz, Raluca Alexandru, Inmaculada Rodriguez, Saioa Arrieta-Aranzueque, David Rimm, Thazin Aung, Kurt A. Schalper, Carlos E. de Andrea, Ignacio Melero

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Figure 6

Xenium spatial transcriptomic analyses of immune related hubs showing associations with T cell functional transcripts.

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Xenium spatial transcriptomic analyses of immune related hubs showing as...
6 representative cases from the CUN melanoma cohort with different densities of cDC1 cells were subjected to Xenium spatial transcriptomic analyses using the PRIME 5K panel. A represents the strategy to define immune related niches by the area of 20-μm diameter (10-μm radius) around an immune cell identified by their key distinguishing transcripts. Niches were classified according to the presence of cDC1 or the absence of cDC1 transcripts. (B) Bar plots showing the density of immune niches with or without cDC1 cells according to clinical benefit. (C) Volcano plot representing the transcripts enriched in immune niches containing cDC1 transcripts versus those without them. (D) Key hand-picked transcripts corresponding to lymphocyte activation (upper panels) and antigen presentation (lower panels), which were differentially expressed in cDC1-rich versus cDC1-devoid immune niches. Point sizes reflect fold change values. The corresponding GSEA according to gene ontology are provided. NES, Normalized Enrichment Scores. (E) Representative images of the immune niches used for analyses with the located transcripts represented by color-coded dots. Circles represent analyzed 20-μm diameter immune niches. On the left, images representing transcripts used to identify cell types and on the right some transcripts denoting T cell activation. The upper images represent an area with cDC1-devoid immune niches and lower images show a representative image of cDC1-enriched immune hubs.