Role of NK and T cells in IL-12-induced anti-tumor response against hepatic colon carcinoma

Abstract

IL‐12 is an immuno‐regulatory cytokine that has been shown to generate a potent NK and Th1 response in a variety of laboratory models. However, the detailed immune development in the hepatic tumor model by IL‐12‐mediated gene therapy has not been clarified. In our previous study, intra‐tumoral transfer of Adv.mIL‐12 (5 × 108 pfu) to the MCA26 colon carcinoma liver tumor induced an effective anti‐tumor response, extending the median survival time from 29 to over 54 days, while 25% of the animals became tumor‐free after a single treatment. In this work, we show that NK cells are responsible for the early, and both NK and T cells for the long‐term, Adv.mIL‐12‐induced immune response. Immuno‐histopathological analysis of the tumor and in vitro cytotoxicity study of the mononuclear cells of the liver show that NK cells are the first to infiltrate and mediate tumor cell killing, as early as 48 hr after Adv.mIL‐12 treatment. In vivo and in vitro depletion of these cells completely abolishes this early anti‐tumor response. This activity can be observed in both populations of conventional NK and NKT cells in vitro and in athymic nude mice in vivo. However, the early NK response alone is not sufficient. In vivo T‐cell depletion in both the primary tumor treatment and the long‐term survival re‐challenge study reveals that T cells in addition to NK cells are required in the development of the long‐term survival and immunity attributed to Adv.mIL‐12 gene therapy in this orthotopic tumor model of colon carcinoma. Int. J. Cancer81:813–819, 1999. © 1999 Wiley‐Liss, Inc.

T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer

“…6 In addition to NK cells, we have shown that T cell participation was mandatory to achieve persistent anti-tumor immunity, and survival of a majority of tumor-bearing animals. 9 In this study, the ability of a treatment that combined triggering of the 4-1BB costimulatory molecule, either with systemic delivery of agonistic anti-4-1BB mAb or intra-tumoral delivery of ADV/4-1BBL, and intratumoral IL-12 gene therapy was tested to induce regression of pre-established breast liver metastases and persistent anti-tumor immunity. Systemic anti-4-1BB mAb alone induced a dramatic tumor regression compared with intra-tumoral delivery of ADV/4-1BBL and adequate controls.…”

“…Seven days later (3 days before virus injection), in vivo CD4 + (purified ascites GK1.5 (ATCC)) or CD8 + T cell (purified ascites 2,43 (ATCC) depletion was performed using specific antibodies, as described previously. 9 Rat Ig was used in control animals after either treatment. Animals received a s.c. challenge of 1 × 10 5 JC parental cells on the flank at day 10 after the virus treatment.…”

“…7,8 Studying the mechanisms of the IL-12-induced antitumor effect, we showed that natural killer (NK) cells were the early and major immune effectors; however, T cell participation was essential for persistence of the antitumor response and long-term survival rates of the animals. 9 4-1BB is a co-stimulatory molecule of the tumor necrosis factor (TNF) receptor superfamily expressed at the surface of activated CD4 + or CD8 + T cells. 10,11 Interaction with its natural 4-1BB ligand (4-1BBL) or agonistic anti-4-1BB antibodies (anti-4-1BB mAb) leads to amplification of T cell-mediated immunity.…”

Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer

“…Although combination therapy resulted in enhanced suppression of local tumor growth, it did not produce increased animal survival in this model. Based on previous studies which suggested that NK cells are largely responsible for the antitumor effects of adenoviral vector-mediated IL-12 gene therapy 4,20 we focused on this activity. However, an investigation into other discrete therapeutic end points revealed interesting differences in AdHSV-tk GCV compared to AdmIL-12 gene therapy.…”

The Role of Glycogen Synthase Kinase 3-β in Immunity and Cell Cycle: Implications in Esophageal Cancer

“…It has been shown that endogenous IL-12 is required not only for resistance to many pathogens but also for chemically induced tumors. Using experimental models, recombinant IL-12 was reported to have a dramatic anti-tumor effect on various tumors including esophageal cancer (Cardenes et al 2010;Mu et al 1995;Pham-Nguyen et al 1999). Moreover, genetic defects in IL-12 production have been shown to predispose individuals to EC (Cardenes et al 2010).…”