Yang, Wang, and Fu et al. profiled 15 responding and 21 non-responding metastatic melanoma tumors and identified 14 cell types and 55 subtypes, including a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC); correlation analysis identified six cellular programs. Higher relative abundance of mregDCs predicted responses to ICI treatment, which was validated in an independent ICI-treated cohort. High mregDC and TCF7+ CD8+ T cell proportions stratified patients’ survival across treatments. Transcriptional, epigenetic, and interactome analysis revealed unique immune-stimulatory and regulatory roles of mregDCs.
Contributed by Shishir Pant
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.
Author Info: (1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. jackie.yang@rutgers.edu. Broad Institute of MIT and Harvard,
Author Info: (1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. jackie.yang@rutgers.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. jackie.yang@rutgers.edu. Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. jackie.yang@rutgers.edu. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. jackie.yang@rutgers.edu. (2) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (8) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Division of Medical Oncology, Department of Medicine, Mass General Brigham, Boston, MA, USA. (11) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (13) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (15) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (18) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Mass General Brigham, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA. Division of Hematology and Oncology, Department of Medicine, Mass General Brigham, Boston, MA, USA. (20) Medical Oncology, Rutgers Cancer Institute, New Brunswick, NJ, USA. (21) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. GMBOLAND@MGH.HARVARD.EDU. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Mass General Brigham, Boston, MA, USA. GMBOLAND@MGH.HARVARD.EDU. (24) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. manoli@mit.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. manoli@mit.edu.
