Modulating the Expression of IFN Regulatory Factor 8 Alters the Protumorigenic Behavior of CD11b+Gr-1+ Myeloid Cells
Modulating the Expression of IFN Regulatory Factor 8 Alters the Protumorigenic Behavior of CD11b+Gr-1+ Myeloid Cells
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DOI：
10.4049/jimmunol.0804132
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发表时间：
2009-07-01
影响因子：
4.4
通讯作者：
Abrams, Scott I.
中科院分区：
文献类型：
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作者：
Stewart, Trina J.;Liewehr, David J.;Abrams, Scott I.
表达CD11b(+)Gr-1（+）的细胞，被称为髓源性抑制细胞，可以介导免疫抑制和肿瘤进展。然而，驱动其致瘤行为的内在分子事件仍有待阐明。尽管CD11b(+)Gr-1（+）细胞在正常小鼠中存在的频率较低，但它们是否在生物学上与携带肿瘤的宿主不同仍未得到解决。这些目的是通过植入（4T1）和原位（小鼠乳腺肿瘤病毒-多瘤病毒中T抗原（MMTV-PyMT））小鼠乳腺癌模型的CD11b(+)Gr-1（+）细胞来研究的。在两种肿瘤模型的CD11b(+)Gr-1（+）细胞及其各自的对照中，观察到与免疫调节相关的标志物的表达存在有限的差异（Cnt）。尽管表型差异有限，但发现肿瘤诱导的CD11b(+)Gr-1（+）细胞比Cnt CD11b(+)Gr-1（+）细胞产生更多的免疫抑制细胞因子谱。此外，当与肿瘤细胞混合时，与来自Cut小鼠的对应细胞相比，来自荷瘤小鼠的CD11b(+)Gr-1（+）细胞显著促进肿瘤生长。然而，当关键的髓系相关转录因子IFN调节因子8的表达增强时，这些肿瘤诱导的CD11b(+)Gr-1（+）细胞的成瘤行为显著减少。这种致瘤作用的丧失独立于宿主免疫系统发生，与CD11b(+)Gr-1（+）细胞因子/趋化因子产生模式相关，类似于非肿瘤小鼠的细胞。总体而言，我们的数据表明，1)两种癌症模型的肿瘤诱导的CD11b（+)Gr-1（+）细胞在表型上相似，但在生物学上与非肿瘤模型不同；2）在肿瘤诱导的CD11b(+)Gr-1（+）细胞中调节IFN调节因子8水平可以显著消除其致瘤行为，这可能对癌症治疗具有重要意义。免疫学杂志，2009,(3):117-128。
CD11b(+)Gr-1(+)-expressing cells, termed myeloid-derived suppressor cells, can mediate immunosuppression and tumor progression. However, the intrinsic molecular events that drive their protumorigenic behavior remain to be elucidated. Although CD11b(+)Gr-1(+) cells exist at low frequencies in normal mice, it also remains unresolved whether they are biologically distinct from those of tumor-bearing hosts. These objectives were investigated using CD11b(+)Gr-1(+) cells from both implantable (4T1) and autochthonous (mouse mammary tumor virus-polyomavirus middle T Ag (MMTV-PyMT)) mouse models of mammary carcinoma. Limited variation was observed in the expression of markers associated with immunoregulation between CD11b(+)Gr-1(+) cells of both tumor models, as well as with their respective controls (Cnt). Despite limited differences in phenotype, tumor-induced CD11b(+)Gr-1(+) cells were found to produce a more immunosuppressive cytokine profile than that observed by Cnt CD11b(+)Gr-1(+) cells. Furthermore, when admixed with tumor cells, CD11b(+)Gr-1(+) cells from tumor-bearing mice significantly enhanced neoplastic growth compared with counterpart cells from Cut mice. However, the protumorigenic behavior of these tumor-induced CD11b(+)Gr-1(+) cells was significantly diminished when the expression of IFN regulatory factor 8, a key myeloid-associated transcription factor, was enhanced. The loss of this protumorigenic effect occurred independently of the host immune system and correlated with a CD11b(+)Gr-1(+) cytokine/chemokine production pattern that resembled cells from nontumor-bearing Cnt mice. Overall, our data indicate that 1) tumor-induced CD11b(+)Gr-1(+) cells from both cancer models were phenotypically similar, but biologically distinct from their nontumor-bearing counterparts and 2) modulation of IFN regulatory factor 8 levels in tumor-induced CD11b(+)Gr-1(+) cells can significantly abrogate their protumorigenic behavior, which may have important implications for cancer therapy. The Journal of Immunology 2009, 183: 117-128.