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Antitumor Activity Mediated by Double-Negative T Cells

¹ Department of Laboratory Medicine and Pathobiology, Multi Organ Transplantation Program, Toronto General Research Institute, University Health Network,
² Department of Immunology, University of Toronto, Toronto, Ontario, Canada

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.

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