Cellular mechanisms of interleukin-12–mediated neuroblastoma regression

Abstract

Background/Purpose: Interleukin-12 (IL-12) is a proinflammatory cytokine with potent antitumor effects. Previous studies from the authors laboratory showed regression of established neuroblastoma in mice vaccinated with IL-12 transduced dendritic cells (DC). Although regression was associated with intense T cell infiltration, the precise role of T cells is unknown. The purpose of this work is to study the cellular mechanisms in IL-12–mediated tumor regression. Methods: Three groups of mice (n = 12) received subcutaneous inoculation with 1 × 106 murine neuroblastoma cells (TBJ). Anti-CD4 (T helper), anti-CD8 (T cytotoxic), or antiasialo-GM1 (natural killer) antibodies were injected intravenously at 3-day intervals to deplete various immune effector cell populations. Mice in each depletion group and the control (nondepleted) group were injected intratumorally on day 7 with 1 × 106 DC IL-12–transduced DC. Tumors were harvested for morphometry and immunohistochemistry at 21 days. Results: CD4 depletion had no effect on tumor growth in either control or IL-12–vaccinated animals. In contrast, CD8-depleted animals treated with IL-12–transduced DC underwent initial regression followed by progressive tumor growth (P <.01). These tumors were smaller in size at the same time-point. However, NK cell depletion (antiasialo GM1) completely abrogated the antitumor effects of IL-12–transduced DC, leading to progressive tumor growth from the outset. There was no difference between the control and treated animals in this group. Conclusions: Contrary to our hypothesis that IL-12 DC primarily function to stimulate a T cell–mediated response, these data suggest that NK cells are essential for the initial antitumor response of animals treated with IL-12–transduced DC. CD8+ T cells appear to be necessary effector cells for complete rejection of tumor and possibly memory. NK cells are responsible for the early immune response. Furthermore, CD4+ (T helper) cells did not play any role in IL-12–induced regression. These results imply that for DC to generate an effective antitumor response against neuroblastoma both acquired and innate effector cells are required. J Pediatr Surg 38:199-204. Copyright 2003, Elsevier Science (USA). All rights reserved.