Antitumor activity mediated by double-negative T cells.
Allogeneic lymphocytes are potent mediators of leukemia and lymphoma remission. The goal of this study was to determine whether single MHC class I locus-mismatched lymphocytes could generate an antilymphoma activity in the absence of graft-versus-host-disease (GVHD) and to understand the underlying mechanisms. Immunoincompetent Scid or lethally irradiated mice were challenged i.v. with a lethal dose of A20 lymphoma cells together with an infusion of single MHC class I locus mismatched splenocytes. Mice that were challenged with A20 cells alone succumbed to lymphoma between 34 and 50 days after infusion. In contrast, >75% of mice that were coinfused with single class I MHC locus mismatched splenocytes survived indefinitely (n = 20) in the absence of GVHD. Interestingly, the number of CD3(+)CD4(-)CD8(-) double-negative (DN) T cells increased 15-fold in mice that did not develop lymphoma. Both DN T cells isolated from the spleens of lymphoma-free mice and DN T cells cloned from naïve mice were cytotoxic to A20 lymphoma cells in vitro. When DN T cell clones were infused into naïve mice i.v. together with A20 lymphoma cells, 86% of recipient mice were protected from lymphoma onset and did not develop GVHD (n = 22). To assess whether the systemic injection of DN T cells can also suppress local tumor development, A20 cells were infused i.m., and at the same time DN T cell clones were infused either i.v. or i.m. Results indicated that DN T cells infused systemically (i.v.) could not prevent local tumor outgrowth, but DN T cells coinfused locally (i.m.) prevented local tumor development in 91% of animals (n = 11). Furthermore, we demonstrate that primary DN T cells were also able to prevent tumor growth in 75% of mice when infused together with A20 cells i.m. (n = 12). Together, these results demonstrate that an antilymphoma activity can be generated in mice without causing GVHD. Furthermore, DN T cells can suppress lymphoma cells in vivo and in vitro, suggesting that DN T cells could be used as a novel strategy for the treatment of lymphoma.
Young
Kevin J
KJ
Department of Laboratory Medicine and Pathobiology, Multi Organ Transplantation Program, Toronto General Research Institute, University Health Network, 621 University Avenue, Toronto, Ontario M5G 2C4, Canada.
Kay
Lyndsey S
LS
Phillips
M James
MJ
Zhang
Li
L
D000818:Animals; D053222:Fas Ligand Protein; D006086:Graft vs Host Disease / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D016867:Immunocompromised Host / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008223:Lymphoma / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D019014:fas Receptor