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 1

Clinical benefit from checkpoint inhibitors is associated with a cDC1 gene signature across checkpoint inhibitor clinical trials for multiple cancer histologies.

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Clinical benefit from checkpoint inhibitors is associated with a cDC1 ge...
(A) Analyses of the gene signature of cDC1 in the tumor biopsy RNA-seq datasets based on XCR1, BATF3, and CLEC9A transcripts from patients participating in the indicated clinical trials and receiving the specified immunotherapy treatments who were classified according to clinical benefit. CR/PR, Complete response or Partial response; SD, Stable disease; PD, Progressive disease. (B and C) similar data analyzed for an NK-cell signature (B) and a signature denoting CD8+ T lymphocytes (C) whose genes are listed. *P < 0.05, **P < 0.01, ***P < 0.001; Wilcoxon significance tests.