title: Cyclophosphamide induces a type I interferon-associated sterile inflammatory response signature in cancer patients' blood cells: implications for cancer chemoimmunotherapy.
abstract: OBJECTIVE
  Certain chemotherapeutics, particularly cyclophosphamide, can enhance the antitumor efficacy of immunotherapy. A better understanding of the cellular and molecular basis of cyclophosphamide-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy.
  
  
  METHODS
  Transcript profiling and flow cytometry were used to explore cyclophosphamide-induced immunoadjuvanticity in patients with hematologic malignancies.
  
  
  RESULTS
  A single high-dose treatment rapidly (1-2 days) induced peripheral blood mononuclear cell (PBMC) transcriptional modulation, leading to reduction of cell-cycle and biosynthetic/metabolic processes and augmentation of DNA damage and cell death pathways (p53 signaling pathway), death-related scavenger receptors, antigen processing/presentation mediators, T-cell activation markers and, noticeably, a type I IFN (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, and BAFF) were increased in patients' plasma. Accordingly, cyclophosphamide induced the expansion/activation of CD14(+)CD16(+) monocytes, of HLA-DR(+), IL-8RA(+), and MARCO(+) monocytes/dendritic cells, and of CD69(+), OX40(+), and IL-8RA(+) lymphocytes.
  
  
  CONCLUSIONS
  Altogether, these data identify the cyclophosphamide-induced immunomodulatory factors in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated with blood cell death, through p53 and IFN-I-related mechanisms.
authors.affiliation: Department of Hematology Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy. federica.moschella@iss.it
authors.forename: Federica
authors.initials: F
authors.lastname: Moschella
authors.forename: Giovanni Fernando
authors.initials: GF
authors.lastname: Torelli
authors.forename: Mara
authors.initials: M
authors.lastname: Valentini
authors.forename: Francesca
authors.initials: F
authors.lastname: Urbani
authors.forename: Carla
authors.initials: C
authors.lastname: Buccione
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Natalino
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Enrico
authors.initials: E
authors.lastname: Proietti
mesh_terms: D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D004249:DNA Damage / Q000187:drug effects; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007167:Immunotherapy; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D007370:Interferon Type I; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; D003520:Cyclophosphamide