Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses
Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses
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DOI：
10.1158/0008-5472.can-07-1063
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Chiocca, E. Antonio
中科院分区：
文献类型：
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作者：
Fulci, Giulia;Dmitrieva, Nina;Chiocca, E. Antonio
临床试验已经证明溶瘤病毒疗法是安全的，但不是有效的。我们已经表明，注射到啮齿动物中建立的颅内胶质瘤中的溶瘤病毒（OV）被迅速清除，这与单核细胞谱系（单核细胞/小胶质细胞/巨噬细胞）细胞的标志物（CD 68和CD 163）的上调有关。然而，目前还不清楚这些细胞是否直接阻碍肿瘤内持久的OV通过吞噬作用，以及他们是否从血液或脑实质浸润肿瘤。为了研究这一点，我们耗尽吞噬细胞与氯膦酸脂质体（CL）在体内通过全身递送和离体在脑切片模型与胶质瘤。有趣的是，全身性CL消耗了动物脾脏和外周血中超过80%的外周CD 163（+）巨噬细胞，从而减少了这些细胞的肿瘤内浸润，但CD 68（+）细胞没有变化。瘤内病毒滴度增加5倍。相比之下，离体CL仅耗尽来自脑切片和肿瘤内的CD 68（+）细胞。病毒滴度增加了10倍。这些数据表明浸润肿瘤的外周CD 163（+）和脑驻留CD 68（+）细胞的吞噬作用直接影响病毒从肿瘤中的清除。因此，改善的治疗功效可能需要调节这些先天免疫细胞。为了支持这一新的治疗模式，我们观察到胶质母细胞瘤患者接受OV治疗后，肿瘤内CD 68（+）和CD 163（+）细胞上调。
Clinical trials have proven oncolytic virotherapy to be safe but not effective. We have shown that oncolytic viruses (OV) injected into intracranial gliomas established in rodents are rapidly cleared, and this is associated with up-regulation of markers (CD68 and CD163) of cells of monocytic lineage (monocytes/microglia/macrophages). However, it is unclear whether these cells directly impede intratumoral persistence of OV through phagocytosis and whether they infiltrate the tumor from the blood or the brain parenchyma. To investigate this, we depleted phagocytes with clodronate liposomes (CL) in vivo through systemic delivery and ex vivo in brain slice models with gliomas. Interestingly, systemic CL depleted over 80% of peripheral CD163(+) macrophages in animal spleen and peripheral blood, thereby decreasing intratumoral infiltration of these cells, but CD68(+) cells were unchanged. Intratumoral viral titers increased 5-fold. In contrast, ex vivo CL depleted only CD68(+) cells from brain slices, and intratumoral. viral titers increased 10-fold. These data indicate that phagocytosis by both peripheral CD163(+) and brain-resident CD68(+) cells infiltrating tumor directly affects viral clearance from tumor. Thus, improved therapeutic efficacy may require modulation of these innate immune cells. In support of this new therapeutic paradigm, we observed intratumoral up-regulation of CD68(+) and CD163(+) cells following treatment with OV in a patient with glioblastoma.