Breaking tolerance to a tumor-associated viral superantigen as a basis forgraft-versus-leukemia reactivity

A major goal in tumor immunotherapy consists of breaking potential tumor-sp ecific T-cell unresponsiveness (tolerance), which may explain tumor growth in cancer patients. We report that immunological tolerance to a tumor-assoc iated viral superantigen (SAg) is overcome in a mouse lymphoma model by tra nsfer of allogeneic T cells expressing SAg-reactive V beta 6 T-cell recepto r chains. Surprisingly, upon contact with SAg-expressing lymphoma cells, V beta 6 T cells became activated rather than tolerized las reported previous ly). They also developed SAg-specific cytotoxic T-lymphocyte activity and s ecreted IL-2 and IFN-gamma, The grafted T cells infiltrated liver metastase s, formed close contact with SAg-expressing tumor cells, and caused signifi cant graft-vs.-leukemia (GvL) effects, Selection for tumor resistance among the progeny from a cross between SAg-negative donor and SAg-positive recip ient strains revealed a strict correlation between loss of the endogenous S Ag tolerogen, rescue of V beta 6 T cells from SAg mediated deletion, and le ukemia resistance. These findings suggest that immune responses to SAg can be exploited to break tolerance and augment immune responses to tumors. (C) 2000 Wiley-Liss, Inc.