title: Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer.
abstract: Fibrocytes are hematopoietic stem cell-derived fibroblast precursors that are implicated in chronic inflammation, fibrosis, and wound healing. Myeloid-derived suppressor cells (MDSCs) expand in cancer-bearing hosts and contribute to tumor immune evasion. They are typically described as CD11b⁺HLA-DR⁻ in humans. We report abnormal expansions of CD11b⁺HLA-DR⁺ myeloid cells in peripheral blood mononuclear fractions of subjects with metastatic pediatric sarcomas. Like classical fibrocytes, they display cell surface α smooth muscle actin, collagen I/V, and mediate angiogenesis. However, classical fibrocytes serve as antigen presenters and augment immune reactivity, whereas fibrocytes from cancer subjects suppressed anti-CD3-mediated T-cell proliferation, primarily via indoleamine oxidase (IDO). The degree of fibrocyte expansion observed in individual subjects directly correlated with the frequency of circulating GATA3⁺CD4⁺ cells (R = 0.80) and monocytes from healthy donors cultured with IL-4 differentiated into fibrocytes with the same phenotypic profile and immunosuppressive properties as those observed in patients with cancer. We thus describe a novel subset of cancer-induced myeloid-derived suppressor cells, which bear the phenotypic and functional hallmarks of fibrocytes but mediate immune suppression. These cells are likely expanded in response to Th2 immune deviation and may contribute to tumor progression via both immune evasion and angiogenesis.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Irena
authors.initials: I
authors.lastname: Maric
authors.forename: Michael J
authors.initials: MJ
authors.lastname: DiPrima
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Rimas J
authors.initials: RJ
authors.lastname: Orentas
authors.forename: Rosandra N
authors.initials: RN
authors.lastname: Kaplan
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D015847:Interleukin-4 / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology*; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000097:blood / Q000276:immunology / Q000473:pathology*; D012512:Sarcoma, Ewing / Q000097:blood / Q000276:immunology / Q000556:secondary*; D018418:Th2 Cells; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D015847:Interleukin-4