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Comparison of the potential therapeutic effects of interleukin 2 or interleukin 4 secretion by a single tumour
P M Patel1, C L Flemming, S J Russell
1Section of Cell and Molecular Biology, London Hospital Medical College, UK.
Abstract:
Engineering of a variety of rodent tumour cells to secrete either interleukin 2 (IL-2), or interleukin 4 (IL-4), has been demonstrated to reduce their tumorigenicity. However the mechanisms of action of secreted IL-2 and IL-4 have not been compared in a single rodent tumour. Here we demonstrate that the weakly immunogenic murine fibrosarcoma FS29 had reduced growth rate and in some cases was rejected by syngeneic animals, when modified to secrete either IL-2 or IL-4, but not IL-5. Immunohistochemical analysis of tumour nodules undergoing regression showed stimulation of a largely lymphocytic infiltrate by IL-2 and a macrophage and granulocyte infiltrate, with a small number of lymphocytes by IL-4. Indeed, secretion of low levels of IL-2 and IL-4 in combination resulted in optimal rejection, suggesting that the two cytokines might mobilise different and complementary effector cell mechanisms. Both IL-2 and IL-4-secreting cells failed to induce the rejection of admixed, unmodified FS29 cells. The loss of cytokine secreting cells from such admixtures occurred more rapidly for IL-2-secreting cells. Injection of IL-4-secreting, but not IL-2-secreting FS29 cells could protect mice from a delayed challenge with unmodified FS29 cells. These data suggest that IL-4 secretion stimulates the better long-term host anti-tumour response.
Insights
Engineering tumors to secrete interleukin-4 (IL-4) showed better long-term anti-tumor responses in mice compared to interleukin-2 (IL-2). Combining IL-2 and IL-4 achieved optimal tumor rejection by mobilizing complementary immune cells.
Area of Science:
- Immunology
- Cancer Biology
- Biotechnology
Background:
- Engineered rodent tumor cells secreting interleukin-2 (IL-2) or interleukin-4 (IL-4) exhibit reduced tumorigenicity.
- Mechanisms of IL-2 and IL-4 in tumor rejection remain incompletely understood and uncompared within a single tumor model.
Purpose of the Study:
- To compare the mechanisms of action of secreted IL-2 and IL-4 in a single rodent tumor model.
- To investigate the potential of cytokine engineering for cancer immunotherapy.
Main Methods:
- Modification of murine fibrosarcoma FS29 cells to secrete IL-2, IL-4, or IL-5.
- Assessment of tumor growth rate and rejection in syngeneic mice.
- Immunohistochemical analysis of tumor-infiltrating immune cells during regression.
- Evaluation of protective immunity against subsequent tumor challenge.
Main Results:
- Both IL-2 and IL-4 secretion reduced FS29 tumor growth and led to rejection in some cases, while IL-5 had no effect.
- IL-2 induced a lymphocytic infiltrate, whereas IL-4 attracted macrophages and granulocytes.
- Combined IL-2 and IL-4 secretion resulted in optimal tumor rejection.
- IL-4-secreting cells, but not IL-2-secreting cells, conferred protection against a secondary tumor challenge.
Conclusions:
- IL-2 and IL-4 employ distinct but complementary immune effector mechanisms for tumor rejection.
- IL-4 secretion appears to stimulate a more robust and durable host anti-tumor immune response, suggesting its potential for long-term cancer immunotherapy.