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Interleukin 12-activated lymphocytes influence tumor genetic programs.
F Cavallo1, E Quaglino, L Cifaldi
1Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy.
Cancer Research
|April 20, 2001
Summary
Activated T-lymphocytes (LYs) modulate tumor genetic programs. Interleukin-12 (IL-12) enhances this effect, with interferon-gamma (IFN-gamma) playing a key role in inhibiting tumor growth and angiogenesis.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- T-lymphocytes (LYs) are crucial immune cells involved in regulating cellular responses.
- Interferon-gamma (IFN-gamma) is a cytokine with known immunomodulatory and anti-tumor properties.
- Understanding how T-lymphocytes influence tumor cell genetics is vital for developing novel cancer therapies.
Purpose of the Study:
- To investigate the capacity of activated T-lymphocytes, with and without Interleukin-12 (IL-12) stimulation, to alter the gene expression profiles of tumor cells.
- To elucidate the specific roles of IFN-gamma and other secreted factors in mediating these T-lymphocyte-induced genetic modulations in tumors.
- To assess the implications of these genetic changes for tumor behavior and potential anti-tumor activity.
Main Methods:
- Activation of T-lymphocytes from normal and IFN-gamma knockout mice using anti-CD3 and anti-CD28 antibodies.
- Co-culture of activated T-lymphocytes with tumor cell lines using transwell systems, with and without IL-12.
- Analysis of gene expression using cDNA arrays, reverse transcription-PCR, and protein expression analysis.
Main Results:
- Factors other than IFN-gamma modulated LPS, transcription termination factor 1, transforming growth factor, and fibroblast growth factor genes.
- High IFN-gamma levels from IL-12-activated LYs up-regulated STAT1, IRF-1, LMP2, LMP7, monokine induced by IFN-gamma, monocyte chemoattractant protein 1, and angiopoietin 2, while down-regulating vascular endothelial growth factor.
- Specific genes like PA28, IFN-inducible protein 10, inducible NO synthetase, and macrophage-inhibitory protein 2 were modulated by IL-12-activated LYs independently of IFN-gamma.
Conclusions:
- IL-12-activated T-lymphocytes significantly alter tumor cell gene expression, including the down-regulation of vascular endothelial growth factor and up-regulation of pro-angiogenic factors.
- These modulations, particularly the interplay between vascular endothelial growth factor and other factors, align with the anti-angiogenic effects observed in IL-12 mediated anti-tumor activity.
- T-lymphocytes actively modify tumor behavior, contributing to their own inhibition through genetic reprogramming of the tumor microenvironment.