Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

Abstract

BackgroundAnti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy.Methods and FindingsWe used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies.ConclusionThe data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.

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

“…Our findings support the role of IFN-I in homeostasis, with crucial implications for patients undergoing myelodepleting regimens, as concomitant treatment with IFN-a could accelerate recovery of immune competence (25). Importantly, although IFN-I induction by CTX is not sufficient for tumor eradication, it is necessary for restoring immune cell pools because the immunopotentiating activity of the drug and the effectiveness of combined CTX/immunotherapies were shown to require endogenous IFN-I to succeed (14,15,41). In this regard, because IFN-I was recently shown to reduce regulatory T cell (Treg) function through stimulation of Agpresenting cells, it is conceivable to speculate a role for endogenous IFN-I in mediating the effects of CTX on Treg ablation (42).…”

“…Among cytokines induced by CTX, type I interferons (IFN-I) mediate many of the effects ascribed to the drug, including the expansion of memory T lymphocytes (12) and the activation of CD11b þ myeloid cells (13). Moreover, the efficacy of combined CTX-immune cell therapy in murine tumors was shown to be strictly dependent on endogenous IFN-I (14,15). Recent studies suggest that CTX immunopotentiating activity can also involve systemic mobilization of DC (16)(17)(18), although the impact of these homeostatic rearrangements on DC-tumor interaction remains elusive.…”

Cytosine Arabinoside Promotes Cytotoxic Effect of T Cells on Leukemia Cells Mediated by Bispecific Antibody

“…In addition, mouse leukemic cells exposed in vivo to Ara-C were more susceptible to CTL-mediated cell killing (Vereecque et al, 2004). This result suggests that the specific antileukemic activity of CTL, acting in synergy with enhanced sensitivity of leukemic cells to immune-mediated cell killing induced by chemotherapy, might eradicate minimal residual disease (van der Most et al, 2009). Accordingly, we hypothesized that cytotoxicity would be enhanced if CTLs were recruited around the tumor cells.…”

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

“…109 Paclitaxel, cisplatin and doxorubicin sensitize tumor cells to CTLs by rendering them permeable to granzyme B via upregulation of mannose-6-phosphate receptors on tumor cell surface. 110 Furthermore, CTX sensitizes tumor cells to TRAIL-dependent CD8 T-cellmediated immune attack, 111 suggesting that TRAIL-mediated tumor cell killing contributes to immunogenic TCD. 112 Platinum derivatives and dacarbazine were shown to stimulate the expression of ligands for NKG2D, an NK cellactivating receptor, resulting in augmented NK-cell cytotoxicity and IFN-g production.…”