Host Immunosurveillance controls tumor growth via IFN regulatory factor-8-dependent mechanisms
Host Immunosurveillance controls tumor growth via IFN regulatory factor-8-dependent mechanisms
复制标题
DOI：
10.1158/0008-5472.can-07-1228
复制
发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Abrams, Scott I.
中科院分区：
文献类型：
--
作者：
Greeneltch, Kristy M.;Schneider, Monika;Abrams, Scott I.
干扰素调节因子（IRF）-8在正常骨髓细胞生成中起重要作用。骨髓细胞中IRF-8的缺失导致慢性髓细胞性白血病样综合征，表明IRF-8在某些造血系统恶性肿瘤中表现为肿瘤抑制基因。我们一直在研究实体瘤进展的分子决定因素，重点是抗凋亡。最近，我们发现IRF-8的表达与Fas介导的细胞凋亡直接相关，与恶性表型呈负相关。然而，IRF-8在实体瘤中的功能作用尚未得到解决。我们在表达IRF-8的小鼠肿瘤细胞中通过RNA干扰稳定沉默IRF-8表达，并评估它们的凋亡表型和恶性行为的变化。尽管增殖、细胞表面Fas或MHC I类分子的表达没有改变，但IRF-8缺陷型肿瘤细胞中Fas参与或辐射诱导的细胞凋亡显著减少。此外，在同基因免疫活性小鼠中，IRF-8缺陷型肿瘤细胞比对照组生长得更具侵略性。然而，在IFN-γ或Fas配体缺陷的小鼠中，而不是T细胞缺陷的小鼠中，对照和IRF-8缺陷的肿瘤群都生长。同样的。此外，两种肿瘤群体在先天免疫缺陷的小鼠中生长相似。尽管随后的研究排除了自然杀伤细胞的作用，但免疫组织化学分析支持巨噬细胞的参与。总之，我们的研究结果表明，实体瘤细胞中的IRF-8表达对于有效的宿主免疫监视和对凋亡刺激的反应是重要的。因此，IRF-8下调可能代表了以前未被认识到的促进肿瘤进展的肿瘤逃逸机制。相反，旨在上调或恢复肿瘤细胞中IRF-8表达的策略可能会提高治疗效果。
IFN regulatory factor (IRF)-8 plays an important role in normal myelopoiesis. The loss of IRF-8 in myeloid cells results in a chronic myelogenous leukemia-like syndrome, suggesting that IRF-8 behaves as a tumor suppressor gene in certain hematopoietic malignancies. We have been investigating the molecular determinants of solid tumor progression, with an emphasis on apoptotic resistance. Recently, we showed that IRF-8 expression was directly correlated with Fas-mediated apoptosis, and inversely related to malignant phenotype. However, the functional role of IRF-8 in solid tumors is unresolved. We stably silenced IRF-8 expression via RNA interference in IRF-8-expressing mouse tumor cells, and evaluated them for changes in apoptotic phenotype and malignant behavior. Apoptosis induced by Fas engagement or irradiation was markedly reduced in IRF-8-deficient tumor cells, despite unaltered proliferation, cell surface Fas, or MHC class I expression. Moreover, in syngeneic immunocompetent mice, IRF-8-deficient tumor cells grew more aggressively than their control counterparts. However, in IFN-gamma- or Fas ligand-deficient mice, but not T cell-deficient mice, both control and IRF-8-deficient tumor populations grew. similarly. Furthermore, both tumor populations grew similarly in mice with defects in innate immunity. Although subsequent studies precluded a role for natural killer cells, immunohistochemical analysis supported the involvement of macrophages. Overall, our findings show that IRF-8 expression in solid tumor cells is important for efficient host immunosurveillance and response to apoptotic stimuli. Therefore, IRF-8 down-regulation may represent a previously unrecognized tumor escape mechanism that facilitates tumor progression. Conversely, strategies aimed at up-regulating or restoring IRF-8 expression in neoplastic cells may improve therapeutic efficacy.