IFN-gamma and Fas ligand are required for graft-versus-tumor activity against renal cell carcinoma in the absence of lethal graft-versus-host disease.
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 10(6) 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-gamma and Fas ligand (FasL), but does not require soluble or membrane-bound TNF-alpha, perforin, or TRAIL. Recipients of IFN-gamma(-/-) 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-gamma(-/-) CD8(+) T cells derived from transplanted mice are less able to kill RENCA cells in vitro, while pretreatment of RENCA cells with IFN-gamma enhances class I and FasL expression and rescues the lytic capacity of IFN-gamma(-/-) 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-gamma and FasL.
Ramirez-Montagut
Teresa
T
Department of Immunology, Laboratory of the Immunology of Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Chow
Andrew
A
Kochman
Adam A
AA
Smith
Odette M
OM
Suh
David
D
Sindhi
Hamad
H
Lu
Sydney
S
Borsotti
Chiara
C
Grubin
Jeremy
J
Patel
Neel
N
Terwey
Theis H
TH
Kim
Theo D
TD
Heller
Glenn
G
Murphy
George F
GF
Liu
Chen
C
Alpdogan
Onder
O
van den Brink
Marcel R M
MR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D020350:Graft vs Tumor Effect / Q000276:immunology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019014:fas Receptor / Q000502:physiology
D053222:Fas Ligand Protein; D019014:fas Receptor; D007371:Interferon-gamma