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Comments on Augmentation of local antitumor immunity in liver by interleukin-2 gene transfer via portal vein: A possible explanation for contradictory in vivo and vitro results of interleukin-2 treatment in a rat model of colon carcinoma metastasis

Cancer Gene Therapy volume 10, pages 432–433 (2003)Cite this article

Tanji et al1 have demonstrated in a rat model that interleukin-2 (IL-2) gene transfer to the liver prevents liver metastasis of colon carcinoma cells. IL-2 gene transfer was performed by intraportal injection of an adenovirus containing the human IL-2 gene (AdCMVhIL-2), before the administration of RCN-9 syngeneic colon carcinoma cells. Controls included injection of either adenovirus containing the β-galactosidase gene or PBS. The authors suggested that hepatic natural killer (NK) cells, which are located in the liver sinusoids,2,3 are responsible for this effect. Indeed, they demonstrated that hepatic NK cells isolated from AdCMVhIL-2 rats showed an increased cytotoxic activity against the NK-sensitive YAC-1 target cell line, confirming the results of Shiratori et al.4 However, they were unable to show an increased cytotoxic effect of these isolated hepatic NK cells against the RCN-9 colon carcinoma cells.1 In other words, the in vivo effects of preventing liver metastasis of RCN-9 colon carcinoma cells in AdCMVIL-2 treated rats did not coincide with an increased activity of hepatic NK cells of these rats against the same target cell line.

We may contribute to a possible explanation for the above-described discrepancy of in vivo and in vitro results. We have shown that rat hepatic NK cells can be subdivided into low-density (LD) and high-density (HD) cells.5 LD cells are found on top of a 45% Percoll gradient, whereas HD cells are pelleted at the bottom. LD cells have been shown to possess the highest cytotoxicity. HD cells possess an intermediate level of cytotoxicity between blood NK and LD cells.5 Highly purified HD cells show a marked response to IL-2 in expressing cytotoxic factors, while LD cells show no or a low response.6 For example, granzyme RNA (RNKP-1 and RNKP-5) is clearly upregulated in HD cells after IL-2 treatment, but not in LD cells.6 Granzymes have been shown to be involved in the killing of colon carcinoma cells by hepatic NK cells.7 Therefore, local IL-2 production in the liver, as applied in the study of Tanji et al, most likely activates the HD cells and to a much lesser extent the LD cells.

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  1. Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, Brussels, 1090, Belgium

    David Vermijlen, Maarten Timmers & Eddie Wisse

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  1. David Vermijlen
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Vermijlen, D., Timmers, M. & Wisse, E. Comments on Augmentation of local antitumor immunity in liver by interleukin-2 gene transfer via portal vein: A possible explanation for contradictory in vivo and vitro results of interleukin-2 treatment in a rat model of colon carcinoma metastasis. Cancer Gene Ther 10, 432–433 (2003). https://doi.org/10.1038/sj.cgt.7700582

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