Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
J Immunol. 2010 Dec 15;185(12):7358-66. doi: 10.4049/jimmunol.1002201. Epub 2010 Nov 12.
We have previously shown that the fusion of GM-CSF and IL-21 (GIFT-21) possesses a potent immune stimulatory effect on myeloid cells. In this study, we define the effect of GIFT-21 on naive murine monocytes (GIFT-21 dendritic cells [DCs]), which express increased levels of Gr-1, CD45R, MHC class I, CD80, CD86, and CXCR4 and suppress CD11c and MHC class II. Compared with conventional dendritic cells, GIFT-21 DCs produced substantially more CCL2, IL-6, TNF-α, and IFN-α and induced significantly greater production of IFN-γ by CD8(+) T cells in MHC class I-restricted Ag presentation assays. B16 melanoma and D2F2 Neu breast cancer growth was inhibited in mice treated with Ag-naive GIFT-21 DCs. This effect was lost in CD8(-/-) and CCR2(-/-) mice and when mice were treated with β(2)-microglobulin-deficient GIFT-21 DCs, indicating that GIFT-21 DCs migrated to and sampled from the tumors to present tumor Ags to CCL2 recruited CD8(+) T cells via MHC class I. We propose that autologous GIFT-21 DCs may serve as a cell therapy platform for the treatment of cancer.
我们之前已经表明，GM-CSF 和 IL-21 的融合（GIFT-21）对髓样细胞具有强大的免疫刺激作用。在这项研究中，我们定义了 GIFT-21 对幼稚的鼠单核细胞（GIFT-21 树突状细胞[DC]）的作用，这些细胞表达高水平的 Gr-1、CD45R、MHC 类 I、CD80、CD86 和 CXCR4，并抑制 CD11c 和 MHC 类 II。与传统的树突状细胞相比，GIFT-21 DC 产生的 CCL2、IL-6、TNF-α 和 IFN-α 显著增加，并且在 MHC 类 I 限制性 Ag 呈递测定中显著诱导 CD8+T 细胞产生 IFN-γ。在接受 Ag 幼稚的 GIFT-21 DC 治疗的小鼠中，B16 黑色素瘤和 D2F2 Neu 乳腺癌的生长受到抑制。在 CD8(-/-)和 CCR2(-/-)小鼠中，这种作用消失，并且当用缺乏β(2)-微球蛋白的 GIFT-21 DC 治疗时，表明 GIFT-21 DC 迁移到肿瘤并从肿瘤中取样以呈递肿瘤 Ag 给 CCL2 募集的 CD8+T 细胞通过 MHC 类 I。我们提出，自体 GIFT-21 DC 可作为癌症治疗的细胞治疗平台。
