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

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. Robitschek, Sandeep K. Yadav, Wentao Deng, Kelly P. Burke, Tatyana Sharova, Ryan J. Sullivan, Sarah Weiss, Kunal Rai, David Liu, Genevieve M. Boland () and Manolis Kellis ()
Additional contact information
Jiekun Yang: Massachusetts Institute of Technology
Cassia Wang: Massachusetts Institute of Technology
Doris Fu: Massachusetts Institute of Technology
Li-Lun Ho: Massachusetts Institute of Technology
Kyriakitsa Galani: Massachusetts Institute of Technology
Lee Chen: Massachusetts Institute of Technology
Jose Gonzalez: Rutgers University-New Brunswick
Jolene Fu: Rutgers University-New Brunswick
Amy Y. Huang: Broad Institute of MIT and Harvard
Dennie T. Frederick: Mass General Brigham
Liang He: Massachusetts Institute of Technology
Mukta Asnani: Rutgers University-New Brunswick
Rahul Tacke: Massachusetts Institute of Technology
Emily J. Robitschek: Broad Institute of MIT and Harvard
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
Tatyana Sharova: Mass General Brigham
Ryan J. Sullivan: Harvard Medical School
Sarah Weiss: Rutgers Cancer Institute
Kunal Rai: University of Texas MD Anderson Cancer Center
David Liu: Broad Institute of MIT and Harvard
Genevieve M. Boland: Broad Institute of MIT and Harvard
Manolis Kellis: Massachusetts Institute of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62878-5

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