Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.
Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.
复制标题
脊髓灰质炎病毒疗法针对恶性神经胶质瘤骨髓浸润，弥漫性小胶质细胞激活吞噬中枢神经系统。
DOI：
10.1093/neuonc/noad052
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发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Gromeier,Matthias
中科院分区：
文献类型：
--
作者：
Yang,Yuanfan;Brown,MichaelC;Zhang,Gao;Stevenson,Kevin;Mohme,Malte;Kornahrens,Reb;Bigner,DarellD;Ashley,DavidM;López,GiselleY;Gromeier,Matthias
背景恶性胶质瘤通过胶质瘤相关的巨噬细胞和小胶质细胞（GAMM）进行致密的炎性浸润，促进免疫抑制、逃避和肿瘤进展。与单核吞噬细胞系统中的所有细胞一样，GAMM组成型表达脊髓灰质炎病毒受体CD 155。除了髓样细胞外，CD 155在恶性胶质瘤的肿瘤区室中广泛上调。使用高度减毒的犀牛：脊髓灰质炎病毒嵌合体PVSRIPO进行肿瘤内治疗，在复发性胶质母细胞瘤患者中获得了长期生存和持久的放射学缓解（Desjardinset al.新英格兰医学杂志，2018）。这种情况提出了关于骨髓细胞与肿瘤细胞对恶性胶质瘤脊髓灰质炎病毒治疗的贡献的问题。MethodsWe调查了PVSRIPO免疫治疗在免疫活性小鼠脑肿瘤模型中的作用，该模型采用盲法，委员会认证的神经病理学家审查，一系列神经病理学，免疫组织化学和免疫荧光分析，以及肿瘤区域的RNAseq。但肿瘤暂时消退在肿瘤周围的正常脑中，在同侧半球并延伸到对侧半球中，这伴随着显著的小胶质细胞活化和增殖。没有恶性细胞溶解性感染的证据。PVSRIPO引发的小胶质细胞活化发生在持续的先天性抗病毒炎症的背景下，与GAMM上程序性细胞死亡配体1（PD-L1）免疫检查点的诱导相关。PVSRIPO与PD 1/PD-L1阻断相结合导致持久的remissions.ConclusionsOur工作牵连GAMM作为PVSRIPO诱导的抗肿瘤炎症的积极驱动程序，并揭示了深刻和广泛的神经炎症激活的脑驻留髓腔PVSRIPO。
BackgroundMalignant gliomas commandeer dense inflammatory infiltrates with glioma-associated macrophages and microglia (GAMM) promoting immune suppression, evasion, and tumor progression. Like all cells in the mononuclear phagocytic system, GAMM constitutively express the poliovirus receptor, CD155. Besides myeloid cells, CD155 is widely upregulated in the neoplastic compartment of malignant gliomas. Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, yielded long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardinset al. New England Journal of Medicine, 2018). This scenario raises questions about the contributions of myeloid versus neoplastic cells to polio virotherapy of malignant gliomas.MethodsWe investigated PVSRIPO immunotherapy in immunocompetent mouse brain tumor models with blinded, board-certified neuropathologist review, a range of neuropathological, immunohistochemical, and immunofluorescence analyses, and RNAseq of the tumor region.ResultsPVSRIPO treatment caused intense engagement of the GAMM infiltrate associated with substantial, but transient tumor regression. This was accompanied by marked microglia activation and proliferation in normal brain surrounding the tumor, in the ipsilateral hemisphere and extending into the contralateral hemisphere. There was no evidence for lytic infection of malignant cells. PVSRIPO-instigated microglia activation occurred against a backdrop of sustained innate antiviral inflammation, associated with induction of the Programmed Cell Death Ligand 1 (PD-L1) immune checkpoint on GAMM. Combining PVSRIPO with PD1/PD-L1 blockade led to durable remissions.ConclusionsOur work implicates GAMM as active drivers of PVSRIPO-induced antitumor inflammation and reveals profound and widespread neuroinflammatory activation of the brain-resident myeloid compartment by PVSRIPO.