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Immune response during tumor therapy with antibody‐superantigen fusion proteins
Author(s) -
Rosendahl Alexander,
Hansson Johan,
Sundstedt Anette,
Kalland Terje,
Dohlsten Mikael
Publication year - 1996
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19960927)68:1<109::aid-ijc19>3.0.co;2-6
Subject(s) - superantigen , cytotoxic t cell , cd8 , immunology , cytokine , immune system , biology , priming (agriculture) , t cell receptor , tumor necrosis factor alpha , t cell , in vitro , biochemistry , botany , germination
To engineer superantigens (SAg) to express tumor reactivity, we genetically fused the Fab‐part of the tumor‐reactive MAb C215 and the bacterial SAg staphylococcal enterotoxin A (SEA). Treatment of mice carrying established lung micrometastases of the C215‐transfected syngeneic B16 melanoma with 3‐4 daily injections of C215Fab‐SEA resulted in strong anti‐tumor effects, while only moderate effects were seen when treatment was given every 4th day (intermittent treatment). High serum levels of IL‐2, TNF‐α, IFN‐γ and strong induction of CTLs (cytotoxic T lymphocytes) were noted after priming with the fusion protein. T cells responded well to 3 daily injections of C215Fab‐SEA and then gradually entered a hyporesponsive state, characterized by a reduced ability to produce IL‐2, TNF‐α and IFN‐γ and failure to mediate cytotoxicity in vitro . Intermittent treatment was characterized by increased levels of IL‐10, concomitant with accentuated loss of IL‐2, TNF‐α and IFN‐γ production. A 10‐fold increase in SEA‐reactive TCR VB3 + CD4 + cells was observed in the spleen, while a loss of TCR VB3 + CD8 + and VB11 + CD8 + cells was noted. This is in striking contrast to injections of native SEA which induced a marked deletion of TCR VB3 + CD4 + T cells, but not of CD8 + cells. Recovery of the THI cytokine profile occurred within 1–2 weeks, while restoration of cytotoxicity required several months and correlated with recovery of TCR VB3 + CD8 + and TCR VB11 + CD8 + T cells. These results show that the temporal relationship of SAg stimulations dictates the cytokine profile. Moreover, different mechanisms appear to regulate hyporesponsiveness in CD4 + and CD8 + T cells. © 1996 Wiley‐Liss, Inc.