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.
Schirrmacher
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German Cancer Research Center, Division of Cellular Immunology, Tumor Immunology Program, Heidelberg, Germany. V.Schirrmacher@dkfz-heidelberg.de
Müerköster
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Bucur
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Umansky
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Rocha
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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