Dacarbazine-Mediated Upregulation of NKG2D Ligands on Tumor Cells Activates NK and CD8 T Cells and Restrains Melanoma Growth
Dacarbazine-Mediated Upregulation of NKG2D Ligands on Tumor Cells Activates NK and CD8 T Cells and Restrains Melanoma Growth
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DOI：
10.1038/jid.2012.273
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发表时间：
2013-02-01
影响因子：
6.5
通讯作者：
Mignot, Gregoire
中科院分区：
文献类型：
--
作者：
Hervieu, Alice;Rebe, Cedric;Mignot, Gregoire
达卡巴嗪（DTIC）是一种广泛用于黑色素瘤治疗的细胞毒性药物。然而，尚未评估抗癌免疫应答对DTIC疗效的假定贡献。通过在黑色素瘤小鼠模型中测试DTIC如何影响宿主对癌症的免疫反应，我们意外地发现自然杀伤（NK）和CD 8（+）T细胞对于DTIC治疗效果是不可或缺的。尽管DTIC不直接影响免疫细胞，但它触发了肿瘤细胞上NKG 2D配体的上调，导致小鼠和人类NK细胞活化和IFN γ分泌。NK细胞衍生的IFN γ随后促进肿瘤细胞上主要组织相容性复合物I类分子的上调，使其对细胞毒性CD 8（+）T细胞敏感。因此，DTIC以NK依赖性方式显著增强体内细胞毒性T淋巴细胞抗原4抑制功效。这些结果强调了DTIC的免疫原性，并为联合收割机DTIC与减轻体内免疫抑制的免疫抑制剂组合提供了理论基础。Journal of Investigative Dermatology（2013）133，499-508; doi：10.1038/jid.2012.273; 2012年9月6日在线发表
Dacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFN gamma secretion in mice and humans. NK cell-derived IFN gamma subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8(+) T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo. Journal of Investigative Dermatology (2013) 133, 499-508; doi:10.1038/jid.2012.273; published online 6 September 2012