Interferon-gamma and CXC chemokine induction by interleukin 12 in renal cell carcinoma

Interleukin 12 (IL-12) is known to play an important role in the developmen t of an antitumor response. Its activity has been shown to be dependent upo n the intermediate production of IFN-gamma and the influx into the tumor of CD8 lymphocytes. In a murine model, tumor regression induced by IL-12 trea tment correlated with IFN-gamma, IP-10, and Mig expression in the tumor bed and was abrogated by antibodies to both chemokines. Here we examined the e ffects of rHuIL-12 on IFN-gamma and CXC chemokine gene expression in patien ts with renal cell carcinoma (RCC) in an attempt to determine whether a sim ilar series of molecular events leading to IL-12-mediated tumor regression in mice is also detectable in humans. As in the murine RENCA model, culture d RCC cells themselves could be induced by IFN-gamma to synthesize IP-10 an d Mig mRNA. Explanted RCC produced IFN-gamma and IP-10 mRNA in response to IL-12 treatment, which was consistent with the finding that biopsied RCC tu mors from IL-12-treated patients also variably expressed augmented If, els of those molecules after therapy. Although Mig mRNA was present in the majo rity of biopsied tumors prior to treatment, both the Mig and IP-10 chemokin es as well as IFN-gamma were induced in the peripheral blood mononuclear ce lls of IL-12-treated patients. Skin biopsies of IL-12-treated patients also all synthesized IP-10 mRNA, This study demonstrates that recombinant human IL-12 therapy of patients with RCC has the potential to induce the express ion of gene products within the tumor bed that may contribute to the develo pment of a successful antitumor response.