Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma
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.
Authors
- Ryan J. Sullivan (ORCID: https://orcid.org/0000-0001-5344-6645)
- Genevieve Marie Boland (ORCID: https://orcid.org/0000-0002-7522-6173)
- Lee Chen
- Tatyana Sharova (ORCID: https://orcid.org/0000-0003-2123-3906)
- Amy Y. Huang (ORCID: https://orcid.org/0000-0002-6646-6503)
- Emily Robitschek (ORCID: https://orcid.org/0000-0002-2771-0155)
- Dennie T. Frederick (ORCID: https://orcid.org/0000-0003-3355-5267)
- Jiekun Yang (ORCID: https://orcid.org/0000-0003-0920-052X)
- Kelly P. Burke (ORCID: https://orcid.org/0000-0003-2187-0147)
- José María González (ORCID: https://orcid.org/0000-0002-1177-869X)
- Sarah A. Weiss (ORCID: https://orcid.org/0000-0002-1106-7089)
- Kunal Rai (ORCID: https://orcid.org/0000-0003-2321-6894)
- Mukta Asnani (ORCID: https://orcid.org/0000-0002-6088-5010)
- Jolene Yin Ling Fu (ORCID: https://orcid.org/0000-0001-8025-0744)
- Wentao Deng (ORCID: https://orcid.org/0000-0001-6501-1737)
- Doris Fu (ORCID: https://orcid.org/0009-0004-7331-6927)
- Manolis Kellis (ORCID: https://orcid.org/0000-0001-7113-9630)
- David Liu (ORCID: https://orcid.org/0000-0003-0346-5033)
- Sandeep Kumar Yadav (ORCID: https://orcid.org/0000-0001-6999-040X)
- Liang He (ORCID: https://orcid.org/0000-0001-6711-2021)
- Li-Lun Ho
- Kyriakitsa Galani
- Cassia Wang
- Rahul Tacke
Institutions
- Rutgers, The State University of New Jersey (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Mass General Brigham (US)
- Massachusetts Institute of Technology (US)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41467-025-62878-5
- Citations
- 7
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 7.32
Funders
- Doris Duke Charitable Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Rutgers, The State University of New Jersey
- Society for Immunotherapy of Cancer