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Transfer of interleukin 2 receptor genes into squamous cell carcinoma. Modification of tumor cell growth
W C Lin1, S Yasumura, T L Whiteside
1Department of Pathology, School of Medicine, University of Pittsburgh, Pa.
Objective:
Human squamous cell carcinomas of the head and neck (SCCHN) have been shown to express interleukin 2 receptor (IL-2R), and binding of the ligand, IL-2, to the receptor results in tumor growth inhibition in vitro or in vivo in an SCCHN xenograft model in nude mice. To optimize growth inhibitory effects of IL-2, expression of the alpha or gamma chains of IL-2R in SCCHN was experimentally modified by transfection of tumor cells with the respective IL-2R genes or the lacZ gene as control.
Design:
Using plasmid vectors containing the IL-2R alpha chain gene under the control of a cytomegalovirus promoter or the IL-2R gamma chain gene under the control of a Rous sarcoma virus promoter, the IL-2R genes were transferred by lipofection into SCCHN cell lines. Stable transfectants were selected, cloned by limiting dilution, and clones were compared with the parental cell lines for their sensitivity to the growth-inhibitory effect of IL-2.
Results:
Transfer of the IL-2R alpha chain gene into SCCHN cells resulted in significant upregulation of expression of the IL-2R alpha chain on tumor cell surface but not in increased tumor growth inhibition by IL-2. In contrast, SCCHN IL-2R gamma transfectants, which expressed IL-2R gamma chain transcripts as confirmed in RNase protection assays, were significantly inhibited in growth and were sensitive to lower concentrations of IL-2 than the parental cell lines.
Conclusions:
Genetic modification of IL-2R expression on IL-2R-positive tumor cells in culture significantly alters their proliferative response to IL-2. These observations open a way for developing new strategies for therapy of SCCHN based on direct interactions of IL-2 with its receptor on tumor cells.
Insights
Modifying interleukin 2 receptor (IL-2R) gamma chain expression in head and neck squamous cell carcinomas enhanced IL-2
Area of Science:
- Immunology and Cancer Research
- Molecular Biology and Genetics
Background:
- Human squamous cell carcinomas of the head and neck (SCCHN) express IL-2R.
- IL-2 binding to IL-2R can inhibit SCCHN tumor growth.
- Optimizing IL-2R expression is key to enhancing therapeutic effects.
Purpose of the Study:
- To investigate the impact of modifying IL-2R alpha and gamma chain expression on SCCHN.
- To determine if genetic modification can enhance IL-2's tumor growth inhibitory effects.
Main Methods:
- SCCHN cell lines were transfected with IL-2R alpha or gamma chain genes using lipofection.
- Stable transfectants were selected and cloned.
- Sensitivity to IL-2's growth-inhibitory effects was compared between transfectants and parental cells.
Main Results:
- IL-2R alpha chain gene transfer upregulated surface expression but did not enhance IL-2's growth inhibition.
- IL-2R gamma chain gene transfer resulted in significant growth inhibition and increased sensitivity to IL-2.
- RNase protection assays confirmed IL-2R gamma chain transcript expression in transfectants.
Conclusions:
- Genetic modification of IL-2R expression significantly alters SCCHN's response to IL-2.
- Enhancing IL-2R gamma chain expression shows promise for SCCHN therapy.
- Direct IL-2 and IL-2R interactions offer novel therapeutic strategies for SCCHN.