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Prophylactic IL-12 treatment reduces postoperative metastasis: mediation by increased numbers but not cytotoxicity of NK cells

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Abstract

Despite a promising potential, interleukin-12 immunotherapy has yielded limited clinical success while causing perilous toxicities. Here we study a context in which IL-12 may prove clinically beneficial—the removal of the primary tumor, when cell-mediated immunity (CMI) may eradicate minimal residual disease (MRD), but is inhibited by postoperative immunosuppression, potentially leading to enhanced malignant progression. F344 rats were preoperatively treated with IL-12 and inoculated postoperatively with syngeneic MADB106 tumor cells. An optimal regimen of eight-day sustained exposure to IL-12 was developed (1 μg/rat/day), which caused mild side effects, increased baseline resistance to experimental MADB106 metastasis, and abolished the promotion of metastasis by laparotomy and other immunosuppressive paradigms. Depletion of NK cells indicated their major role in controlling MADB106 metastasis in naïve and IL-12 treated rats. Studying NK cytotoxicity, we found that IL-12 did not potentiate activity per NK cell, nor protected it from suppression by surgery. However, IL-12 increased the numbers of NK cells in the circulation and marginating pulmonary pool of naïve and operated rats, and correspondingly increased total NK activity in these compartments. Therefore, this study indicates anti-tumor effects of IL-12 based on increased numbers of strategically located NK cells, and advocates a prophylactic approach against the potential metastasis-promoting effects of surgery.

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Abbreviations

CMI:

cell-mediated immunity

MP:

metaproterenol

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Acknowledgements

This research was supported by NIH/NCI grant CA73056 and by a grant from the Israel Science Foundation to Dr. S. Ben-Eliyahu.

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  1. Department of Psychology, Neuroimmunology Research Unit, Tel Aviv University, Tel Aviv, 69978, Israel

    Yossi Schwartz, Roi Avraham, Marganit Benish, Ella Rosenne & Shamgar Ben-Eliyahu

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  1. Yossi Schwartz
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  2. Roi Avraham
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  5. Shamgar Ben-Eliyahu
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Correspondence to Shamgar Ben-Eliyahu.

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Schwartz, Y., Avraham, R., Benish, M. et al. Prophylactic IL-12 treatment reduces postoperative metastasis: mediation by increased numbers but not cytotoxicity of NK cells. Breast Cancer Res Treat 107, 211–223 (2008). https://doi.org/10.1007/s10549-007-9540-9

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