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Perforin and IFN-γ are involved in the antitumor effects of antibody- targeted superantigens

Rosendahl, Alexander ; Kristensson, Karin ; Hansson, Johan ; Riesbeck, Kristian LU orcid ; Kalland, Terje and Dohlsten, Mikael (1998) In Journal of Immunology 160(11). p.5309-5313
Abstract

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- γ and TNF-α in serum. In the present study we have characterized the molecular mechanisms of the antitumor effect induced by Fab-SEA treatment in vivo.... (More)

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- γ and TNF-α 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-γ in the suppression of tumor growth. In addition, a minor contribution of TNF-α 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-γ. The latter mechanism may have an important role in cytostatic effects against Ag-negative bystander tumor cells.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Journal of Immunology
volume
160
issue
11
pages
5309 - 5313
publisher
American Association of Immunologists
external identifiers
  • scopus:0032104007
  • pmid:9605129
ISSN
0022-1767
language
English
LU publication?
no
id
4d84ec84-45ac-4662-9a70-765160e8df8d
alternative location
https://www.jimmunol.org/content/jimmunol/160/11/5309.full.pdf
date added to LUP
2019-06-07 15:23:34
date last changed
2024-03-19 12:06:08
@article{4d84ec84-45ac-4662-9a70-765160e8df8d,
  abstract     = {{<p>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- γ and TNF-α 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-γ in the suppression of tumor growth. In addition, a minor contribution of TNF-α 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-γ. The latter mechanism may have an important role in cytostatic effects against Ag-negative bystander tumor cells.</p>}},
  author       = {{Rosendahl, Alexander and Kristensson, Karin and Hansson, Johan and Riesbeck, Kristian and Kalland, Terje and Dohlsten, Mikael}},
  issn         = {{0022-1767}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{11}},
  pages        = {{5309--5313}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of Immunology}},
  title        = {{Perforin and IFN-γ are involved in the antitumor effects of antibody- targeted superantigens}},
  url          = {{https://www.jimmunol.org/content/jimmunol/160/11/5309.full.pdf}},
  volume       = {{160}},
  year         = {{1998}},
}