Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNγ is mediated by both CD8+ and CD4+ T-cells
Cure of established GL261 mouse gliomas after combined immunotherapy with GM-CSF and IFNγ is mediated by both CD8+ and CD4+ T-cells
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DOI：
10.1002/ijc.23986
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发表时间：
2009-02-01
影响因子：
6.4
通讯作者：
Siesjo, Peter
中科院分区：
文献类型：
--
作者：
Smith, Karin Enell;Fritzell, Sara;Siesjo, Peter
我们首次证明了用产生GM-CSF的GL 261细胞和预先建立的GL 261胶质瘤的重组IFN γ的联合免疫疗法可以治愈90%的免疫小鼠。为了扩展这些发现并揭示潜在的机制，进行了随后的实验。我们假设GM-CSF和IFN γ全身联合免疫会增加未成熟骨髓细胞的数量，然后这些细胞会成熟并分化为树突状细胞（DC）和巨噬细胞，从而增强肿瘤抗原呈递和T细胞活化。事实上，联合治疗诱导了未成熟和成熟骨髓细胞的系统性增加，但也增加了T调节细胞（T-T细胞）。在用GM-CSF和IFN γ免疫后，通过颗粒酶B阳性细胞以及产生IFN γ的T细胞的增加反映的细胞毒性抗肿瘤应答增强。我们还表明，联合治疗诱导了长期记忆与脑内（即）再挑战T细胞的消耗表明，CD 4（+）和CD 8（+）T细胞对于GM-CSF和IFN γ的组合效应是必需的。最后，当免疫接种延迟至肿瘤接种后第5天时，只有接受GM-CSF和IFN γ免疫治疗的小鼠存活。我们的结论是，除了重组IFN γ与GM-CSF生产的肿瘤细胞的免疫接种增加了活化的肿瘤杀伤T细胞的数量，这可以根除建立脑内肿瘤。这些结果清楚地表明，细胞因子的组合在脑肿瘤的免疫治疗中具有协同效应，这对人类恶性脑肿瘤的临床免疫治疗具有意义。(C)2008 Wiley-Liss，Inc.
We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFN gamma of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFN gamma systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation. Indeed, the combined therapy induced a systemic increase of both immature and mature myeloid cells but also an increase in T regulatory cells (T-regs). Cytotoxic anti-tumor responses, mirrored by an increase in Granzyme B-positive cells as well as IFN gamma-producing T-cells, were augmented after immunizations with GM-CSF and IFN gamma. We also show that the combined therapy induced a long-term memory with rejection of intracerebral (i.e.) rechallenges. Depletion of T-cells showed that both CD4(+) and CD8(+) T-cells were essential for the combined GM-CSF and IFN gamma effect. Finally, when immunizations were delayed until day 5 after tumor inoculation, only mice receiving immunotherapy with both GM-CSF and IFN gamma survived. We conclude that the addition of recombinant IFN gamma to immunizations with GM-CSF producing tumor cells increased the number of activated tumoricidal T-cells, which could eradicate established intracerebral tumors. These results clearly demonstrate that the combination of cytokines in immunotherapy of brain tumors have synergistic effects that have implications for clinical immunotherapy of human malignant brain tumors. (C) 2008 Wiley-Liss, Inc.