Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that exhibits specific tumoricidal activity against a variety of tumors1,2. It is expressed on different cells of the immune system and plays a role in natural killer cell–mediated tumor surveillance3,4,5. In allogeneic hematopoietic-cell transplantation, the reactivity of the donor T cell against malignant cells is essential for the graft-versus-tumor (GVT) effect6. Cytolytic activity of T cells is primarily mediated through the Fas–Fas ligand and perforin–granzyme pathways. However, T cells deficient for both Fas ligand and perforin can still exert GVT activity in vivo in mouse models7,8. To uncover a potential role for TRAIL in donor T cell–mediated GVT activity, we compared donor T cells from TRAIL-deficient and wild-type mice in clinically relevant mouse bone-marrow transplantation models. We found that alloreactive T cells can express TRAIL, but the absence of TRAIL had no effect on their proliferative and cytokine response to alloantigens. TRAIL-deficient T cells showed significantly lower GVT activity than did TRAIL-expressing T cells, but no important differences in graft-versus-host disease, a major complication of allogeneic hematopoietic cell transplantation, were observed. These data suggest that strategies to enhance TRAIL-mediated GVT activity could decrease relapse rates of malignancies after hematopoietic cell transplantation without exacerbation of graft-versus-host disease.
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We thank the staff of the Research Animal Resource Center for animal care; M.-A. Perales for assistance with intracellular cytokine staining; H. Nguyen for expertise with the histopathologic examination of tissue specimen; G. Heller for statistical help; and R.J. O'Reilly and A. Houghton for helpful discussions and support throughout the project. This work was supported by grants HL69929 and HL72412 from the National Institutes of Health (to M.R.M.v.d.B.). C.S. is a Special Fellow of the Leukemia and Lymphoma Society. M.R.M.v.d.B. is the recipient of a Damon Runyan Scholar Award of the Cancer Research Fund and a research award from the V scholar program of the V Foundation.
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Combining naturally occurring polyphenols with TNF-related apoptosis-inducing ligand: a promising approach to kill resistant cancer cells?
Cellular and Molecular Life Sciences (2010)