Perforin and IFN-gamma are involved in the antitumor effects of antibody-targeted superantigens.
The bacterial superantigen staphylococcal enterotoxin A (SEA) is a potent inducer of cytokine production and cytotoxic T cell responses. To target a T cell attack against tumor cells we have genetically engineered a fusion protein of SEA and the Fab part of the tumor-reactive mAb C215. Injection of this Fab-SEA fusion protein to mice carrying lung metastases of the poorly immunogenic B16 melanoma transfected with the C215 Ag resulted in infiltration of cytokine-producing T cells, perforin-containing CTL, and a marked tumor elimination. Fab-SEA therapy induced substantial levels of IFN-gamma and TNF-alpha in serum. In the present study we have characterized the molecular mechanisms of the antitumor effect induced by Fab-SEA treatment in vivo. Neutralization of cytokines by specific Abs demonstrated a major role for IFN-gamma in the suppression of tumor growth. In addition, a minor contribution of TNF-alpha was recorded. Injections of Fab-SEA into normal mice induced strong CTL activity but failed to promote cytotoxic function in perforin knockout mice. Also, a markedly reduced therapy was noted in perforin knockout mice, implicating a role for CTL in Fab-SEA-mediated tumor eradication. The data suggest that Fab-SEA-targeted T cells may suppress tumor growth by both perforin-dependent cytotoxicity and local release of cytokines such as IFN-gamma. The latter mechanism may have an important role in cytostatic effects against Ag-negative bystander tumor cells.
Rosendahl
A
A
Pharmacia & Upjohn, Lund Research Center, Sweden. alexander.rosendahl@eu.pnu.com
Kristensson
K
K
Hansson
J
J
Riesbeck
K
K
Kalland
T
T
Dohlsten
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000276:immunology* / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004768:Enterotoxins / Q000235:genetics / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004768:Enterotoxins; D006131:Growth Inhibitors; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma