Cyclophosphamide Synergizes with Type I Interferons through Systemic Dendritic Cell Reactivation and Induction of Immunogenic Tumor Apoptosis

Abstract

Successful chemotherapy accounts for both tumor-related factors and host immune response. Compelling evidence suggests that some chemotherapeutic agents can induce an immunogenic type of cell death stimulating tumor-specific immunity. Here, we show that cyclophosphamide (CTX) exerts two types of actions relevant for the induction of antitumor immunity in vivo: (i) effect on dendritic cell (DC) homeostasis, mediated by endogenous type I interferons (IFN-I), leading to the preferential expansion of CD8a þ DC, the main subset involved in the cross-presentation of cell-derived antigens; and (ii) induction of tumor cell death with clear-cut immunogenic features capable of stimulating tumor infiltration, engulfment of tumor apoptotic material, and CD8 T-cell cross-priming by CD8a þ DC. Notably, the antitumor effects of CTX were efficiently amplified by IFN-I, the former providing a source of antigen and a "resetting" of the DC compartment and the latter supplying optimal costimulation for T-cell cross-priming, resulting in the induction of a strong antitumor response and tumor rejection. These results disclose new perspectives for the development of targeted and more effective chemoimmunotherapy treatments of cancer patients. Cancer Res; 71(3); 768-78. Ó2010 AACR.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…CTX exerted its effects preferentially on the CD8a-expressing-DC subset, determining an initial ablation of lymphoid organ-resident CD8a þ DCs, followed by overshoot replenishment after drug discontinuation. 20,21 Data from our laboratory have revealed that, after CTX administration, CD8a þ DCs migrate to the tumor site where they cross-present tumor-associated antigen ( Figure 2). The platinum-based compound cisplatin was also reported to modulate the percentages of myeloid cells by increasing DCs and eliminating myeloid-derived suppressor cells (MDSCs), thus favoring immune effector responses in melanoma-bearing mice.…”

“…94 The degree of TCD correlates with clinical outcome in several tumor settings. 95,96 Some chemotherapeutics, including anthracyclines, oxaliplatin and CTX, are unique in their capacity to induce an immunogenic type of TCD, 21,97 thereby converting dying tumor cells into adjuvanted-endogenous vaccines. The rational base of vaccination is that tumor antigens must be captured by activated DCs, which would activate CD4 and CD8 T-cell-mediated adaptive immune responses.…”

“…100 Similarly to anthracyclines, some alkylating agents have also been shown to induce an immunogenic TCD that stimulates antigen cross-presentation by DC, and CD8 T-cell crosspriming. 21,101 Seldom, non-apoptotic death pathways are also induced by chemotherapy with mechanisms that are now beginning to be explained. Some alkylating agents (nitrogen mustard and N-methyl-N-nitro-N-nitrosoguanidine) induce necrosis, an unregulated process rising from acute cellular stress or massive cell injury.…”

“…118 Furthermore, although high-dose CTX kills BM-resident DC precursors, thus hampering DC mobilization at the peripheral level, 119,120 these precursors are resistant to low-dose CTX, which instead boosts the differentiation of mature DCs in vivo and ex vivo. 21,121,122 Of note, CTX-induced mobilization and maturation of DCs from their BM precursors was mediated by endogenous type I IFN. 21,55,123 Other non-immune targets of cytotoxic chemotherapy are the endothelial cells.…”

“…21,121,122 Of note, CTX-induced mobilization and maturation of DCs from their BM precursors was mediated by endogenous type I IFN. 21,55,123 Other non-immune targets of cytotoxic chemotherapy are the endothelial cells. Indeed, the collateral damage inflicted upon dividing endothelial cells within the tumor bed indirectly Off-target effects of chemotherapy L Bracci et al helps tumor destruction.…”