Cyclophosphamide Induces a Type I Interferon―Associated Sterile Inflammatory Response Signature in Cancer Patients' Blood Cells: Implications for Cancer Chemoimmunotherapy

• Published in: Clinical cancer research 2013-08, Vol.19 (15), p.4249-4261
• Main Authors: MOSCHELLA, Federica, TORELLI, Giovanni Fernando, VALENTINI, Mara, URBANI, Francesca, BUCCIONE, Carla, PETRUCCI, Maria Teresa, NATALINO, Fiammetta, BELARDELLI, Filippo, FOA, Robin, PROIETTI, Enrico
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; DNA Damage - drug effects; Flow Cytometry; Gene Expression Profiling; Humans; Immunity - drug effects; Immunotherapy; Inflammation - chemically induced; Inflammation - genetics; Inflammation - pathology; Interferon Type I - metabolism; Interferon-gamma - metabolism; Medical sciences; Monocytes - drug effects; Monocytes - pathology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-3666

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. Transcript profiling and flow cytometry were used to explore cyclophosphamide-induced immunoadjuvanticity in patients with hematologic malignancies. 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. 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.