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Clin Cancer Res. 2013 Aug 1;19(15):4249-61. doi: 10.1158/1078-0432.CCR-12-3666. Epub 2013 Jun 12.

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

Author information

1
Department of Hematology Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy. federica.moschella@iss.it

Abstract

PURPOSE:

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.

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 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.

PMID:
23759676
DOI:
10.1158/1078-0432.CCR-12-3666
[Indexed for MEDLINE]
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