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Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma

Author

Listed:
  • Jiekun Yang

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard
    Rutgers University-New Brunswick
    Rutgers University-New Brunswick)

  • Cassia Wang

    (Massachusetts Institute of Technology)

  • Doris Fu

    (Massachusetts Institute of Technology)

  • Li-Lun Ho

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

  • Kyriakitsa Galani

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

  • Lee Chen

    (Massachusetts Institute of Technology)

  • Jose Gonzalez

    (Rutgers University-New Brunswick
    Rutgers University-New Brunswick)

  • Jolene Fu

    (Rutgers University-New Brunswick
    Rutgers University-New Brunswick)

  • Amy Y. Huang

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Dennie T. Frederick

    (Mass General Brigham)

  • Liang He

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

  • Mukta Asnani

    (Rutgers University-New Brunswick
    Rutgers University-New Brunswick)

  • Rahul Tacke

    (Massachusetts Institute of Technology)

  • Emily J. Robitschek

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Sandeep K. Yadav

    (University of Texas MD Anderson Cancer Center)

  • Wentao Deng

    (University of Texas MD Anderson Cancer Center)

  • Kelly P. Burke

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Tatyana Sharova

    (Mass General Brigham)

  • Ryan J. Sullivan

    (Harvard Medical School
    Mass General Brigham)

  • Sarah Weiss

    (Rutgers Cancer Institute)

  • Kunal Rai

    (University of Texas MD Anderson Cancer Center)

  • David Liu

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Genevieve M. Boland

    (Broad Institute of MIT and Harvard
    Mass General Brigham)

  • Manolis Kellis

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet most patients fail to achieve durable responses. To better understand the tumor microenvironment (TME), we analyze single-cell RNA-seq (~189 K cells) from 36 metastatic melanoma samples, defining 14 cell types, 55 subtypes, and 15 transcriptional hallmarks of malignant cells. Correlations between cell subtype proportions reveal six distinct clusters, with a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC) linked to naive T and B cells. Importantly, mregDC abundance predicts progression-free survival (PFS) with ICIs and other therapies, especially when combined with the TCF7 + /– CD8 T cell ratio. Analysis of an independent cohort (n = 318) validates mregDC as a predictive biomarker for anti-CTLA-4 plus anti-PD-1 therapies. Further characterization of mregDCs versus conventional dendritic cells (cDC1/cDC2) highlights their unique transcriptional, epigenetic (single-nucleus ATAC-seq data for cDCs from 14 matched samples), and interaction profiles, offering new insights for improving immunotherapy response and guiding future combination treatments.

Suggested Citation

  • Jiekun Yang & Cassia Wang & Doris Fu & Li-Lun Ho & Kyriakitsa Galani & Lee Chen & Jose Gonzalez & Jolene Fu & Amy Y. Huang & Dennie T. Frederick & Liang He & Mukta Asnani & Rahul Tacke & Emily J. Robi, 2025. "Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62878-5
    DOI: 10.1038/s41467-025-62878-5
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    References listed on IDEAS

    as
    1. Paul C. Tumeh & Christina L. Harview & Jennifer H. Yearley & I. Peter Shintaku & Emma J. M. Taylor & Lidia Robert & Bartosz Chmielowski & Marko Spasic & Gina Henry & Voicu Ciobanu & Alisha N. West & M, 2014. "PD-1 blockade induces responses by inhibiting adaptive immune resistance," Nature, Nature, vol. 515(7528), pages 568-571, November.
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