Rapid recruitment of macrophages in interleukin‐12‐mediated tumour regression

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Abstract
In order to study the mechanism of interleukin‐12 (IL‐12) antitumour activity, RH7777 rat hepatoma cells were engineered to express mouse IL‐12 (mIL‐12) (RH7777/mIL‐12) under the tight control of doxycycline (dox). The production of the mIL‐12 protein was regulated by the concentration of dox that was present in the culture medium. RH7777/mIL‐12 cells appeared to have the same tumorigenic activity as did parental RH7777 cells, when subcutaneously injected into syngeneic rat (BUF/N) in the absence of dox. However, the tumorigenicity of RH7777/mIL‐12, but not RH7777, cells were significantly decreased when dox was administrated to the animals. In addition, established tumours of RH7777/mIL‐12 cells gradually disappeared upon the induction of mIL‐12 by dox. To elucidate the kinetic profile of immune cells involved in the mIL‐12‐induced tumour regression, both histological and immunohistochemical analyses were performed 1, 3 and 14 days after the dox treatment on rats bearing tumours that were approximately 0·5 cm in diameter. Tumour‐infiltrating macrophages began to appear at the tumour site one day after dox treatment. As time elapsed, the number of tumour infiltrates including CD4+, CD8+, natural killer (NK) cells and macrophages gradually increased. In particular, CD8+ and NK cells constituted the major population of the tumour‐infiltrated cells. Furthermore, it was found that resting peritoneal macrophages (PM) from rats were chemoattracted in response to mIL‐12. The effects of mIL‐12 on PM chemotaxis were reproducibly observed in concentrations as low as 0·1 ng/ml. These findings suggest that IL‐12 can directly recruit macrophages into tumour sites which, in turn, leads to a broad and intense immunological response against tumour.

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