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

Problems of Cancer Treatment. Part 2. Treatment Based on Modification of Anticancer Immunological Responses in Therapy

“…In this case, the observed therapeutic effect resembled that noted following administration of autovaccine of in vitro irradiated leukaemic cells [33,37,47]. Also administration of dendritic cells was suggested as an anti-neoplastic vaccine [34,53], the effect of which might be amplified by low doses of chemotherapeutic drugs [59].…”

“…However, another approach to the problem is possible: tumour cells, similarly to normal cells may die due to apoptosis. Administration to the patient of cells of his own antigens, in the form of extracts, tumour lysates, viable cells with induced apoptosis may provide autovaccine and it provides the patient with objective clinical responses more frequently (in 8.1% of the patients ) in various tumours than in patients following therapy employing individual tumour antigens (a response in 3.6% patients) [47]. Administration of autovaccine leads to presentation to lymphocytes T of the current tumour cell epitopes; current since a neoplastic tumour consists of various pathologically altered cells and the scope of their antigens alters during tumour development.…”

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…104 In patients with hematological malignancies, the administration of high-dose cyclophosphamide induced a rapid, transient and broad transcriptional modulation on peripheral blood mononuclear cells resulting in DNA damage, cell death and, noticeably, a Type-I-IFN signature. 106 This promoted the establishment of a systemic sterile inflammatory response characterized by the release of endogenous adjuvant signals able to enhance the efficacy of immunotherapy. 106 Similar to chemotherapy, radiation therapy was also reported to increase the levels of Type-I-IFNs and CXCL10 in the TME.…”

“…106 This promoted the establishment of a systemic sterile inflammatory response characterized by the release of endogenous adjuvant signals able to enhance the efficacy of immunotherapy. 106 Similar to chemotherapy, radiation therapy was also reported to increase the levels of Type-I-IFNs and CXCL10 in the TME. 107 In this study, CXCL10 was shown to promote tumor CD8 C T cell-homing and cytolytic activity.…”

High-dose cyclophosphamide induces specific tumor immunity with concomitant recruitment of LAMP1/CD107a-expressing CD4-positive T cells into tumor sites

“…We observed that infiltrated CD4 + T cells consistently expressed constantly higher levels of LAMP1/CD107a and additional inflammatory cytokines, particularly type I interferon [10,26,27]. CTX can enhance the expression of IL-2 [28] and type I interferon [29]. Thus, once CD4 + T Naito 15 cells entered into tumor sites, these cells differentiated into CD4 + CTLs under the influence of these cytokines.…”