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Transfer of the interleukin-2 gene into human cancer cells induces specific
antitumor recognition and restores the expression of CD3/T- cell receptor
associated signal transduction molecules
A Guarini, L Riera, A Cignetti, L Montacchini, M Massaia and R Foa
Dipartimento di Scienze Biomediche ed Oncologia Umana, University of
Torino, Italy.
Normal peripheral blood mononuclear cells (PBMC) were co-cultured with a
human lung cancer cell line (LC89) transduced with the interleukin-2
(IL-2), IL-7, granulocyte-macrophage colony-stimulating factor (GM- CSF),
and tumor necrosis factor-alpha (TNF-alpha) genes to evaluate the capacity
of the engineered cells to: allow survival of CD3+ and CD56+ cells,
generate cytotoxic effectors with HLA class I restricted and unrestricted
antitumor activity, and interfere in the molecular organization of the
CD3/T-cell receptor associated signal transduction machinery. When PBMC
were cultured up to 3 weeks with IL-2 releasing LC89 cells (LC89/IL-2), the
number of viable CD3+ and CD56+ lymphocytes was much greater than in
cultures with parental cells or with LC89 cells transduced with the other
cytokine genes. After 1 week of coculture, a variable degree of restricted
and unrestricted killing directed against different targets was observed.
When the cultures were prolonged up to 3 weeks, LC89/IL-2 cells induced a
marked increase in specific cytotoxic activity, which was coupled to a
further enhancement of unrestricted lytic function. In the presence of
LC89/IL-7 cells the degree of specific lysis remained unchanged, whereas
unrestricted effectors were markedly decreased. No cytotoxic activity could
be induced by LC89/GM-CSF and LC89/TNF-alpha cells in the few lymphocytes
surviving after 3 weeks of culture. Coculture of parental LC89 cells with
PBMC was consistently associated with a downmodulation in the expression of
the CD3 zeta chain, as well as of the tyrosine kinases p56ick and ZAP-70.
On the contrary, LC89/IL-2 cells, and not LC89 cells transduced with the
IL-7, GM-CSF, or TNF-alpha gene, were capable of reverting the
immunosuppressive effect exerted by the tumor cells. This protective effect
could be maintained in cultures prolonged up to 4 weeks. When the same
cultures were set up in Transwell, ie, with a membrane separation between
cancer cells and PBMC, the expression of the CD3 zeta chain and of the
p56ick and ZAP-70 tyrosine kinases remained unchanged under all culture
conditions, indicating that the downmodulation of T-cell signal
transduction molecules requires a direct cell to cell contact. These
results show that transfer of the IL- 2 gene into the DNA of human cancer
cells promotes both restricted and unrestricted antitumor activity, and is
capable of restoring and maintaining the expression of molecules involved
in the process of T- cell mediated tumor cell recognition, thus underlining
the potential role of the IL-2 gene in the design of vaccination protocols
with cytokine gene transduced cancer cells.
Volume 89,
Issue 1,
pp. 212-218,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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