Mature and Migratory Dendritic Cells Promote Immune Infiltration and Response to Anti-Pd-1 Checkpoint Blockade in Metastatic Melanoma

Authors

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
Manolis Kellis

Publication Date

9-1-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-62878-5

PMID

40890106

PMCID

PMC12402436

PubMedCentral® Posted Date

9-1-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Melanoma, Dendritic Cells, Humans, Immune Checkpoint Inhibitors, Tumor Microenvironment, Programmed Cell Death 1 Receptor, Cell Movement, CD8-Positive T-Lymphocytes, Female, Male

Published Open-Access

yes

Recommended Citation

Yang, Jiekun; Wang, Cassia; Fu, Doris; et al., "Mature and Migratory Dendritic Cells Promote Immune Infiltration and Response to Anti-Pd-1 Checkpoint Blockade in Metastatic Melanoma" (2025). Faculty, Staff and Student Publications. 4964.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4964