Redlinger Richard E, Shimizu Takashi, Remy Thierry, Alber Sean, Watkins Simon C, Barksdale Edward M
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
J Pediatr Surg. 2003 Feb;38(2):199-204. doi: 10.1053/jpsu.2003.50043.
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.
Three groups of mice (n = 12) received subcutaneous inoculation with 1 x 10(6) 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 x 10(6) DC IL-12-transduced DC. Tumors were harvested for morphometry and immunohistochemistry at 21 days.
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.
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.
背景/目的：白细胞介素-12（IL-12）是一种具有强大抗肿瘤作用的促炎细胞因子。作者实验室先前的研究表明，用IL-12转导的树突状细胞（DC）接种的小鼠体内，已形成的神经母细胞瘤出现消退。尽管消退与强烈的T细胞浸润有关，但T细胞的确切作用尚不清楚。这项工作的目的是研究IL-12介导的肿瘤消退中的细胞机制。
三组小鼠（n = 12）皮下接种1×10⁶个小鼠神经母细胞瘤细胞（TBJ）。每隔3天静脉注射抗CD4（辅助性T细胞）、抗CD8（细胞毒性T细胞）或抗唾液酸GM1（自然杀伤细胞）抗体，以耗尽各种免疫效应细胞群体。每个耗竭组和对照组（未耗竭）的小鼠在第7天瘤内注射1×10⁶个DC IL-12转导的DC。在第21天收获肿瘤进行形态计量学和免疫组织化学分析。
CD4耗竭对对照组或接种IL-12的动物的肿瘤生长均无影响。相反，用IL-12转导的DC处理的CD8耗竭动物最初肿瘤消退，随后肿瘤进行性生长（P <.01）。在同一时间点，这些肿瘤体积较小。然而，NK细胞耗竭（抗唾液酸GM1）完全消除了IL-12转导的DC的抗肿瘤作用，导致肿瘤从一开始就进行性生长。该组中对照组和处理组动物之间没有差异。
与我们关于IL-12 DC主要起刺激T细胞介导反应作用的假设相反，这些数据表明NK细胞对于用IL-12转导的DC处理的动物的初始抗肿瘤反应至关重要。CD8⁺ T细胞似乎是完全排斥肿瘤并可能形成记忆所必需的效应细胞。NK细胞负责早期免疫反应。此外，CD4⁺（辅助性T）细胞在IL-12诱导的消退中未发挥任何作用。这些结果意味着DC要产生针对神经母细胞瘤的有效抗肿瘤反应，既需要获得性效应细胞也需要先天性效应细胞。
