Human Monocytes - CD14, CD16 - Ziegler-Heitbrock

Contact

Cyclophosphamide induces a type I interferon-associated sterile inflammatory response signature in cancer patients' blood cells: implications for cancer chemoimmunotherapy

Abstract

PURPOSE: Certain chemotherapeutics, particularly cyclophosphamide, can enhance the anti-tumor efficacy of immunotherapy. A better understanding of the cellular and molecular basis of cyclophosphamide-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. EXPERIMENTAL DESIGN: 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 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), of death-related scavenger receptors, of antigen processing/presentation mediators, of T-cell activation markers and, noticeably, of a type I interferon (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, BAFF) were increased in patients' plasma. Accordingly, cyclophosphamide induced the expansion/activation of CD14+CD16+ monocytes, of HLA-DR+, IL-8RA+, MARCO+ monocytes/dendritic cells and of CD69+, OX40+, 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 to blood cell death, through p53 and IFN-I-related mechanisms.

Authors: Moschella F, Torelli GF, Valentini M, Urbani F, Buccione C, Petrucci MT, Natalino F, Belardelli F, Foa R, Proietti E
Journal: Clin Cancer Res. ;19(15):4249-61
Year: 2013
PubMed: Find in PubMed