Dunsmore et al. used inducible tdTomato monocyte labeling to probe the emergence of tumor-associated macrophage (TAM) subsets enriched in mouse PDAC. An intermediate CCR2+CD64+ population emerged from monocytes at early time points (~7 days), expressed a chemotactic program, and gave rise to two distinct, terminally differentiated TAM subsets. TAM2 (CD73+) were regulated by the TF Maf, and localized to hypoxic regions near the tumor core. TAM3 (TREM2+) exhibited gene programs associated with lipid handling, and resided outside the tumor core in a mutually exclusive region from TAM2. Similar TAM populations and spatial patterns were identified in human PDAC.
Contributed by Morgan Janes
ABSTRACT: Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC.
Author Info: (1) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Université Paris-Saclay, Ile-de-France, France. (2) S
Author Info: (1) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Université Paris-Saclay, Ile-de-France, France. (2) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (3) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (4) Quantitative Systems Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. (5) Curtin Medical School, Curtin University, Bentley, WA, Australia. (6) Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3, Singapore 138648, Singapore. (7) Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3, Singapore 138648, Singapore. (8) Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3, Singapore 138648, Singapore. (9) Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3, Singapore 138648, Singapore. (10) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. (11) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (12) Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC Université Paris Cité, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France. (13) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Université Paris-Saclay, Ile-de-France, France. (14) Quantitative Systems Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. (15) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. (16) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Université Paris-Saclay, Ile-de-France, France. (17) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Université Paris-Saclay, Ile-de-France, France. (18) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. (19) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. (20) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (21) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (22) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. (23) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (24) Laboratory of Immunophysiology, GIGA Institute, Liège University, Liège, Belgium. Faculty of Veterinary Medicine, Liège University, Liège, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. (25) Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC Université Paris Cité, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France. (26) Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC Université Paris Cité, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris, France. (27) Curtin Medical School, Curtin University, Bentley, WA, Australia. Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, 6 Verdun Street, Nedlands, Perth, WA 6009, Australia. Institute of Molecular and Cellular Biology, A*STAR, Singapore 138673, Singapore. KK Research Centre, KK Women's and Children's Hospital, Singapore 229899, Singapore. Translational Genomics Program, Garvan Institute of Medical Research and Kinghorn Cancer Centre, Darlinghurst, NSW, Australia. (28) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (29) Quantitative Systems Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. (30) Shanghai Immune Therapy Institute Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200010, China. Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore. (31) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Institut Necker Enfants Malades (INEM), CNRS UMR 8253, INSERM U1151, 160 rue de Vaugirard, 75015 Paris, France. (32) Institut Gustave Roussy, INSERM U1015, Bâtiment de Médecine Moléculaire 114 rue Edouard Vaillant, 94800 Villejuif, France. Université Paris-Saclay, Ile-de-France, France. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3, Singapore 138648, Singapore. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 Singapore.
