Antitumor and antimetastatic effects of interleukin 12.

Interleukin 12 (IL-12) has a pivotal role in controlling cell-mediated immunity through a number of important biological activities, such as secretion of interferon-gamma (IFN-gamma). In this review, we report our recent results regarding the antitumor and antimetastatic effects of IL-12. Five intraperitoneal injections of recombinant IL-12 (rIL-12) into mice bearing subcutaneous tumors (CSA1M fibrosarcoma) induced complete tumor regression, irrespective of whether tumors were at early or late stages of growth. Furthermore, IL-12-treated mice that had rejected the primary tumor exhibited complete resistance to rechallenge with the same tumor but did not reject a second syngeneic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T-cells had infiltrated 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 systemic administration of anti-IFN-gamma monoclonal antibody prior to IL-12 treatment completely abrogated the antitumor effect of IL-12. We next investigated the ability of rIL-12 to modulate the outgrowth of metastatic tumor cells in an ovarian carcinoma (OV-HM) model. This aggressive tumor showed rapid growth of the primary tumor mass, a high incidence of metastases to the lung and lymph nodes, and invasion from the primary subcutaneous site into the peritoneal cavity. At approximately 1 month after tumor implantation, primary tumors in animals without palpable lymph nodes were surgically resected. When examined 2 months later, most animals had developed lymph node and lung metastases. In contrast, rIL-12 injections following tumor resection inhibited the development of metastases in both the lung and lymph nodes. Even in mice showing signs of lymph node metastases or invasion of the abdominal wall before primary tumor resection, rIL-12 administration following tumor resection prevented further invasion into the peritoneal cavity and metastatic tumor cell growth in the lung. Our results demonstrate that administration of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving efficient IFN-gamma production by antitumor T-cells at tumor sites in situ and the establishment of a tumor-specific protective immune response. The results also indicate that IL-12 can induce a curative immune response in the face of an aggressive micrometastasizing tumor.