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and Fas Ligand Are Required for Graft-versus-Tumor Activity against Renal Cell Carcinoma in the Absence of Lethal Graft-versus-Host Disease1
* Department of Immunology and Department of Medicine, Laboratory of the Immunology of Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Howard Hughes Medical Institute, Laboratory of Neuro-oncology, The Rockefeller University, New York, NY 10021;
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115; and
¶ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32608
To determine the mechanisms of graft-versus-tumor (GVT) activity in the absence of graft-versus-host disease (GVHD) against a solid tumor, we established two allogeneic bone marrow transplantation models with a murine renal cell carcinoma (RENCA). The addition of 0.3 x 106 donor CD8+ T cells to the allograft increased the survival of tumor-bearing mice without causing GVHD. The analysis of CD8+ T cells deficient in cytotoxic molecules demonstrated that anti-RENCA activity is dependent on IFN-
and Fas ligand (FasL), but does not require soluble or membrane-bound TNF-
, perforin, or TRAIL. Recipients of IFN-–/– CD8+ T cells are unable to reject RENCA compared with recipients of wild-type CD8+ T cells and, importantly, neither group develops severe GVHD. IFN-–/– CD8+ T cells derived from transplanted mice are less able to kill RENCA cells in vitro, while pretreatment of RENCA cells with IFN- enhances class I and FasL expression and rescues the lytic capacity of IFN-–/– CD8+ T cells. These results demonstrate that the addition of low numbers of selected donor CD8+ T cells to the allograft can mediate GVT activity without lethal GVHD against murine renal cell carcinoma, and this GVT activity is dependent on IFN- and FasL.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants HL69929, HL72412, and CA33049 from the National Institutes of Health and awards from the Leukemia and Lymphoma Society, Emerald Foundation and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research.
2 Address correspondence and reprint requests to Dr. Marcel M. R. van den Brink, Laboratory of Allogeneic Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center, Z1404, Box 111, 1275 York Avenue, New York, NY 10021. E-mail address: vandenbm{at}mskcc.org
3 Abbreviations used in this paper: allo-BMT, allogeneic bone marrow transplantation; GVL, graft-versus-leukemia; GVHD, graft-versus-host disease; FasL, Fas ligand; GVT, graft-versus-tumor; RENCA, renal cell carcinoma; BMT, bone marrow transplantation; BM, bone marrow; BLI, bioluminescence imaging; AUC, area under the curve; TCD-BM, T cell-depleted BM; WT, wild type; memTNF, membrane-bound form of TNF-; DLI, donor leukocyte infusion; DAB, diaminobenzidine.
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  K. Ishiyama, A. Takami, S. Suzuki, H. Konaka, M. Namiki, A. Ooi, and S. Nakao Relationship Between Tumor-infiltrating T Lymphocytes and Clinical Response After Reduced-intensity Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Renal Cell Carcinoma: A Single Center Prospective Study Jpn. J. Clin. Oncol., September 20, 2009; (2009) hyp104v1. [Abstract] [Full Text] [PDF]
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