TRAIL‐induced cell death cooperates with IFN‐γ activation in the graft‐versus‐tumor effect against colon tumors

Abstract

The graft-versus-tumor (GVT) effect that occurs following allogeneic bone marrow transplantation (BMT) and donor lymphocyte infusion (DLI) is currently being subjected to intensive investigation because of clinical evidence for GVT efficacy against leukemia. In this report, we investigate the efficacy and molecular mechanisms of GVT against solid tumors, using a modification of the mouse parent-to-F1 BMT model. Mouse Colon26 cells in which tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor expression was stably knocked down were transplanted to investigate the role of the TRAIL-TRAIL receptor system in the GVT effect. In addition, Fas ligand-(FasL) deficient mice on a C57BL6 (B6) background were used as donors, to determine the significance of the Fas-FasL system for the antitumor effect. The group that received B6 DLI followed by preconditioning with 950 rad irradiation underwent tumor reduction associated with the induction of IFN-c, TRAIL and tumor-cell apoptosis. In vitro cultured Colon26 cells were resistant to TRAIL but susceptible to the combination of IFN-c and TRAIL in a TRAILdose-dependent manner. The infusion of lymphocytes from FasLdefective donors reduced the tumor progression, although efficacy was decreased in the TRAIL receptor knockdown tumors but not in wild-type ones, compared with infusion of B6-derived lymphocytes. The findings indicate that GVT activity against subcutaneous colon tumors is efficiently induced by preconditioning with irradiation and allogeneic DLI, and that TRAIL and IFN-c act cooperatively in the antitumor effect. ' 2005 Wiley-Liss, Inc.Key words: graft-versus-host disease; bone marrow transplantation; donor lymphocyte infusion; Fas ligandThe combination of allogeneic bone marrow transplantation (BMT) and donor lymphocyte infusion (DLI) represents a potentially curative therapy for patients with hematological malignancies. The antileukemic effect of this approach has been substantiated by clinical evidence; much of the therapeutic potential is related to the graft-versus-leukemia (GVL) effect, in addition to the effects of high doses of chemoradiation therapy before transplantation. Since GVL effects are closely associated with graftversus-host disease (GVHD), which is a life-threatening complication of BMT, the possibility of distinguishing GVHD from GVL has recently become the focus of intensive research. [1][2][3][4] In solid tumors, as opposed to hematological tumors, the malignant cells are enmeshed in a stroma that consists of a complex network of microvasculature and extracellular matrix. As the stroma prevents the effective priming of CTLs, solid cancer cells are often ''immunologically ignored'' and free from immunological rejection. 5,6 Although the feasibility of inducing a graft-versustumor (GVT) effect against solid cancers has already been suggested in some clinical studies, 7,8 the efficacy of this approach and the molecular mechanisms underlying it remain unclear. Previous reports have demonstrated that GVL activities are mediated by na...

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Activated monocytes augment TRAIL‐mediated cytotoxicity by human NK cells through release of IFN‐γ

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