Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells.
Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells.
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发表时间：
1996-05
期刊：
影响因子：
11.2
通讯作者：
C. Armstrong;R. Botella;T. H. Galloway;Nancy B. Murray;Jill Kramp;I. S. Song;J. Ansel
中科院分区：
文献类型：
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作者：
C. Armstrong;R. Botella;T. H. Galloway;Nancy B. Murray;Jill Kramp;I. S. Song;J. Ansel
免疫调节基因疗法在恶性疾病治疗中的应用正在深入研究中。在这项研究中，我们在小鼠模型中检测了黑色素瘤来源的粒细胞-巨噬细胞集落刺激因子（GM-CSF）抑制黑色素瘤进展的潜力。将小鼠GM-CSF基因在SV40表达载体中转染HGH18小鼠黑色素瘤细胞系，产生产生不同量GM-CSF的黑色素瘤克隆。用HFH18亲代黑色素瘤细胞或非编码3‘-5’方向转染GM-CSF基因的HFH18细胞（HFH18/GM-CSF（-）细胞）接种sc的同基因小鼠，在第30天形成大肿瘤，平均肿瘤体积达到3300 mm3。相比之下，接种了两个产生高水平GM-CSF的黑色素瘤克隆[HFH18/GM-CSF（++）和HFH18/GM-CSF(++ +)]的动物要么完全排斥肿瘤细胞，要么发展成平均体积仅为40 mm3的肿瘤。相比之下，接种产生低水平GM-CSF [HFH18/GM-CSF(+)]的黑色素瘤克隆的动物产生平均为2000 mm3的大肿瘤，从而证明黑色素瘤来源的GM-CSF抑制肿瘤的剂量反应效应。此外，用辐照过的产生gm - csf的黑色素瘤细胞接种疫苗，对随后的HFH18细胞攻击具有最佳的免疫原性。切除的产生GM-CSF的肿瘤细胞接种部位的组织切片，而不是来自HFH18亲本或HFH18/GM-CSF（-）接种部位的组织切片显示，密集的炎症浸润由中性粒细胞、组织巨噬细胞和大量CD4和cd8阳性淋巴细胞组成，但很少有黑色素瘤细胞。大量树突状细胞和表达B7-2共刺激分子的细胞仅在HFH18/GM-CSF（+ + +）黑色素瘤接种部位检测到。我们的研究结果进一步支持GM-CSF基因疗法治疗晚期恶性黑色素瘤的临床试验，可能通过募集树突状抗原呈递细胞。
The use of immunomodulating gene therapy in the treatment of malignant disease is under intensive investigation. In this study, we examined the potential of melanoma-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) to inhibit melanoma progression in a murine model. The HGH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clones that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected with the GM-CSF gene n the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm3 by day 30. In contrast, animals inoculated with two melanoma clones producing high levels of GM-CSF [HFH18/GM-CSF(++) and HFH18/GM-CSF(+ + +)] either completely reject the tumor cells or develop tumors with a mean volume of only 40 mm3. In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] develop large tumors averaging 2000 mm3, thus demonstrating a dose-response effect of tumor inhibition by melanoma-derived GM-CSF. Additionally, vaccination with irradiated GM-CSF-producing melanoma cells conferred optimal immunogenicity against a subsequent challenge with HFH18 cells. Tissue sections from excised GM-CSF-producing tumor cell inoculation sites but not from HFH18 parental or HFH18/GM-CSF(-) inoculation sites demonstrate a dense inflammatory infiltrate composed of neutrophils, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells. Large numbers of dendritic cells and cells expressing the B7-2 costimulatory molecule are detected only within HFH18/GM-CSF(+ + +) melanoma inoculation sites. Our results lend further support to clinical trials of GM-CSF gene therapy in the treatment of advanced malignant melanoma, possibly by the recruitment of dendritic antigen-presenting cells.