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Are Involved in the Antitumor Effects of Antibody-Targeted Superantigens
*
Pharmacia & Upjohn, Lund Research Center, and
Department of Cell and Molecular Biology, Lund University, Lund, Sweden
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-
and
TNF-
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- in the suppression of tumor
growth. In addition, a minor contribution of TNF- 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-. The latter mechanism may have an important role in
cytostatic effects against Ag-negative bystander tumor cells.
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