Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan R C
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43. doi: 10.1073/pnas.90.8.3539.
To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.
为了比较不同细胞因子和其他分子增强肿瘤细胞免疫原性的能力，我们构建了10种编码潜在免疫调节剂的逆转录病毒，并研究了由这些病毒转导的小鼠肿瘤细胞的疫苗接种特性。在B16黑色素瘤模型中，单独照射的肿瘤细胞不会刺激显著的抗肿瘤免疫，我们发现表达小鼠粒细胞-巨噬细胞集落刺激因子（GM-CSF）的照射肿瘤细胞能刺激强大、持久且特异性的抗肿瘤免疫，这需要CD4+和CD8+细胞共同参与。表达白细胞介素4和6的照射细胞也能刺激可检测到但较弱的活性。与B16系统不同，我们发现在许多其他肿瘤模型中，先前在涉及活的、转导细胞的细胞因子基因转移研究中报道的抗肿瘤免疫水平，仅通过使用照射细胞即可实现。然而，通过调整疫苗或攻击剂量，也能够在这些系统中证明小鼠GM-CSF的活性。总体而言，我们的结果对于基因改造肿瘤细胞作为治疗性癌症疫苗的临床应用具有重要意义。
