Dorigo O, Shawler D L, Royston I, Sobol R E, Berek J S, Fakhrai H
Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, 90095-1740, USA.
Gynecol Oncol. 1998 Nov;71(2):204-10. doi: 10.1006/gyno.1998.5151.
The immunosuppressive protein transforming growth factor beta (TGF-beta) inhibits the activation of various immune effector cells including cytotoxic T lymphocytes and may therefore inhibit the efficacy of immunostimulatory interleukin-2 (IL-2) gene therapy. In this study, we investigated the effect of TGF-beta downregulation on IL-2 gene therapy in the intraperitoneal model of murine ovarian teratoma (MOT). MOT cells, like many human ovarian carcinomas, were found to produce TGF-beta. Production of TGF-beta by MOT cells was suppressed using a TGF-beta antisense plasmid vector (pCEP4/TGF-beta antisense). Subcutaneous immunization of C3H mice with a mixture of IL-2 gene-transduced fibroblasts and TGF-beta antisense-modified MOT cells induced significantly better protection against a subsequent intraperitoneal tumor challenge compared with immunization with unmodified MOT cells alone [11/16 (69%) vs 4/21 (19%) tumor-free animals, P < 0.01]. Immunization with either a mixture of IL-2 gene modified fibroblasts and unmodified MOT cells [2/12 (17%) tumor-free animals] or TGF-beta antisense-modified MOT cells alone (0/13 tumor free animals) failed to induce significant protection compared with immunization with unmodified MOT cells. These data show that combined TGF-beta antisense and IL-2 gene therapy is required to generate effective antitumor responses in the MOT model. Our findings suggest that tumor cell expression of immunosuppressive factors may inhibit cytokine immunogene therapy and may have potential implications for the development of future clinical immunogene therapy protocols.
免疫抑制蛋白转化生长因子β（TGF-β）可抑制包括细胞毒性T淋巴细胞在内的多种免疫效应细胞的激活，因此可能会抑制免疫刺激性白细胞介素-2（IL-2）基因治疗的疗效。在本研究中，我们在小鼠卵巢畸胎瘤（MOT）的腹腔模型中研究了TGF-β下调对IL-2基因治疗的影响。发现MOT细胞与许多人类卵巢癌一样会产生TGF-β。使用TGF-β反义质粒载体（pCEP4/TGF-β反义）抑制MOT细胞产生TGF-β。与单独用未修饰的MOT细胞免疫相比，用IL-2基因转导的成纤维细胞和TGF-β反义修饰的MOT细胞混合物对C3H小鼠进行皮下免疫，可诱导对随后腹腔肿瘤攻击的显著更好的保护作用[无瘤动物为11/16（69%）对4/21（19%），P<0.01]。与用未修饰的MOT细胞免疫相比，用IL-2基因修饰的成纤维细胞和未修饰的MOT细胞混合物[2/12（17%）无瘤动物]或单独用TGF-β反义修饰的MOT细胞（0/13无瘤动物）免疫均未能诱导出显著的保护作用。这些数据表明，在MOT模型中需要联合TGF-β反义治疗和IL-2基因治疗以产生有效的抗肿瘤反应。我们的研究结果表明，免疫抑制因子的肿瘤细胞表达可能会抑制细胞因子免疫基因治疗，并且可能对未来临床免疫基因治疗方案的开发具有潜在意义。
