Breaking tolerance to a tumor-associated viral superantigen as a basis for graft-versus-leukemia reactivity.
A major goal in tumor immunotherapy consists of breaking potential tumor-specific T-cell unresponsiveness (tolerance), which may explain tumor growth in cancer patients. We report that immunological tolerance to a tumor-associated viral superantigen (SAg) is overcome in a mouse lymphoma model by transfer of allogeneic T cells expressing SAg-reactive Vbeta6 T-cell receptor chains. Surprisingly, upon contact with SAg-expressing lymphoma cells, Vbeta6 T cells became activated rather than tolerized (as reported previously). They also developed SAg-specific cytotoxic T-lymphocyte activity and secreted IL-2 and IFN-gamma. The grafted T cells infiltrated liver metastases, formed close contact with SAg-expressing tumor cells, and caused significant graft-vs. -leukemia (GvL) effects. Selection for tumor resistance among the progeny from a cross between SAg-negative donor and SAg- positive recipient strains revealed a strict correlation between loss of the endogenous SAg tolerogen, rescue of Vbeta6 T cells from SAg-mediated deletion, and leukemia resistance. These findings suggest that immune responses to SAg can be exploited to break tolerance and augment immune responses to tumors.
German Cancer Research Center, Division of Cellular Immunology, Tumor Immunology Program, Heidelberg, Germany. V.Schirrmacher@dkfz-heidelberg.de
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D019264:Adoptive Transfer; D000818:Animals; D000956:Antigens, Viral / Q000096:biosynthesis / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007426:Genes, Intracisternal A-Particle; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D011533:Proviruses / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D018089:Superantigens / Q000096:biosynthesis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; C095378:Mtv-7 superantigen, Mouse mammary tumor virus; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens