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 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 patients9 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. Clin Cancer Res; 19(15); 4249–61. ©2013 AACR .