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 o ur recent results regarding the antitumor and antimetastatic effects o f IL-12. Five intraperitoneal injections of recombinant IL-12 (rIL-12) into mice bearing subcutaneous tumors (CSAlM fibrosarcoma) induced co mplete tumor regression, irrespective of whether tumors were at early or late stages of growth. Furthermore, IL-12-treated mice that had rej ected the primary tumor exhibited complete resistance to rechallenge w ith the same tumor but did not reject a second syngeneic tumor. Immuno histochemical analyses following IL-12 treatment revealed that CD4(+) and CD8(+) T-cells had infiltrated the tumor. More importantly, IFN-ga mma mRNA expression was observed in fresh tumor masses from tumor-bear ing mice receiving IL-12 treatment. The importance of IFN-gamma was fu rther 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 abi lity 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 t he lung and lymph nodes, and invasion from the primary subcutaneous si te into the peritoneal cavity. At approximately 1 month after tumor im plantation, primary tumors in animals without palpable lymph nodes wer e surgically resected. When examined 2 months later, most animals had developed lymph node and lung metastases. In contrast, rIL-12 injectio ns following tumor resection inhibited the development of metastases i n both the lung and lymph nodes. Even in mice showing signs of lymph n ode metastases or invasion of the abdominal wall before primary tumor resection, rIL-12 administration following tumor resection prevented f urther invasion into the peritoneal cavity and metastatic tumor cell g rowth in the lung. Our results demonstrate that administration of rIL- 12 to tumor-bearing mice results in tumor regression through mechanism s involving efficient IFN-gamma production by antitumor T-cells at tum or sites in situ and the establishment of a tumor-specific protective immune response. The results also indicate that IL-12 can induce a cur ative immune response in the face of an aggressive micrometastasizing tumor.