SYSTEMIC ADMINISTRATION OF RIL-12 INDUCES COMPLETE TUMOR-REGRESSION AND PROTECTIVE IMMUNITY - RESPONSE IS CORRELATED WITH A STRIKING REVERSAL OF SUPPRESSED IFN-GAMMA PRODUCTION BY ANTITUMOR T-CELLS

Unfractionated spleen cells taken from tumor-bearing mice 2 weeks afte r tumor implantation contained tumor-primed T cells which produced cyt okines including IL-2 and IFN-gamma when cultured in vitro. With progr essive tumor growth this initial lymphokine-producing capacity decreas ed. Here, we investigated the ability of IL-12 to (i) restore suppress ed IFN-gamma production, (ii) cause tumor regression and (ii) induce a nti-tumor protective immunity. Addition of rIL-12 to spleen cell cultu res from 4- to 10-week-old tumor-bearing mice resulted in a striking e nhancement in the production of IFN-gamma compared with cultures of th ese cells in the absence of rIL-12 or of normal spleen cells in the pr esence of rIL-12, Five i.p. injections of rIL-12 into mice bearing s.c . tumors induced complete tumor regression, This was found when rIL-12 was given at early (1-2 weeks), intermediate (4-5 weeks) or even late (7 weeks) stages of tumor growth. Furthermore, IL-12-treated mice whi ch rejected the primary tumor exhibited complete resistance to a recha llenge with the same tumor but did not reject a second syngenetic tumo r. Immunohistochemical analyses following IL-12 treatment revealed tha t CD4(+) and CD8(+) T cells infiltrate the tumor. More importantly, IF N-gamma mRNA expression was observed in fresh tumor masses from tumor- bearing mice receiving IL-12 treatment. The importance of IFN-gamma wa s further demonstrated by the observation that the systemic administra tion of anti-IFN-gamma mAb prior to IL-12 treatment completely abrogat ed the anti-tumor effect of IL-12. Thus, these results indicate that a dministration of modest levels of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving reversal of suppress ed IFN-gamma production by anti-tumor T cells and the establishment of a tumor-specific protective immune response.