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

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 cyclophosphamideinduced 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. © 2013 American Association for Cancer Research.