Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-γ production by anti-tumor T cells

Abstract

Unfractionated spleen cells taken from tumor-bearing mice 2 weeks after tumor implantation contained tumor-primed T cells which produced cytokines including IL-2 and IFN-gamma when cultured in vitro. With progressive tumor growth this initial lymphokine-producing capacity decreased. Here, we investigated the ability of IL-12 to (i) restore suppressed IFN-gamma production, (ii) cause tumor regression and (ii) induce anti-tumor protective immunity. Addition of rIL-12 to spleen cell cultures from 4- to 10-week-old tumor-bearing mice resulted in a striking enhancement in the production of IFN-gamma compared with cultures of these cells in the absence of rIL-12 or of normal spleen cells in the presence 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 which rejected the primary tumor exhibited complete resistance to a rechallenge with the same tumor but did not reject a second syngenetic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T cells infiltrate the tumor. More importantly, IFN-gamma mRNA expression was observed in fresh tumor masses from tumor-bearing mice receiving IL-12 treatment. The importance of IFN-gamma was further demonstrated by the observation that the systemic administration of anti-IFN-gamma mAb prior to IL-12 treatment completely abrogated the anti-tumor effect of IL-12. Thus, these results indicate that administration of modest levels of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving reversal of suppressed IFN-gamma production by anti-tumor T cells and the establishment of a tumor-specific protective immune response.

Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively, synergizes to facilitate regression of established tumors

“…35 In fact, this notion was supported recently by the observations that IL -12-induced tumor regression is blocked by neutralizing IFN -produced after IL-12 injections. 36,37 Tumor rejection involves a number of processes: sensitization /activation of effector T cells with tumor antigens in lymphoid organs; migration of T cells together with other effector cells to tumor masses; and tumor cell attack by these tumorinfiltrating effectors. To study the role of IFN -, we grew J558 tumors in IFN -KO mice and treated these tumors with intratumoral coinjection of AdVIP -10 and AdVIL -18.…”

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

“…IL-12 is considered as an important antitumor cytokine, which has potent antitumor effects in mouse models of melanoma, sarcoma, kidney cancer, lung cancer, colon cancer, and ovarian cancer [89][90][91][92][93][94]. Systemic or peritumoral injection of IL-12 is capable of inducing complete regression of established tumors, limiting the formation of distant metastases, and substantially prolonging the survival of mice harboring a tumor [95].…”

“…Systemic or peritumoral injection of IL-12 is capable of inducing complete regression of established tumors, limiting the formation of distant metastases, and substantially prolonging the survival of mice harboring a tumor [95]. In some tumor models, mice experiencing complete responses after IL-12 therapy were subsequently able to reject transplants of the same tumor, but not of a different tumor, which indicates that specific antitumor immunity had been established in those mice [90,92,93,96]. IL-12 was found to be more effective and/or less toxic than IL-2 in models of colon, ovarian, lung, and renal cell cancer along with melanoma [90][91][92]97].…”

Molecular cloning of cat interleukin-12

“…It is therefore a key regulatory molecule in T-helper-cell type-1 (Th-1)-driven immune responses that are considered necessary for the elimination of intracellular pathogens (Scott and Kaufman 1991). In vivo administered IL-12 has powerful antitumor and antimetastatic activity (Brunda et al 1993;Zou et al 1995) and is a promising vaccine adjuvant (Afonso et al 1994;Schijns et al 1995;Wynn et al 1995). Due to its inhibitory effects on IL-4 and IgE synthesis, IL-12 may be considered in the prevention of IgE-mediated allergic conditions (Kiniwa et al 1992).…”