脊髓灰质炎病毒疗法以弥漫性小胶质细胞激活浸润的恶性神经胶质瘤髓样细胞为靶点，吞噬中枢神经系统。
Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.
机构信息
Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Neurosurgery, Duke University Medical School, Durham, NC, USA.
出版信息
Neuro Oncol. 2023 Sep 5;25(9):1631-1643. doi: 10.1093/neuonc/noad052.
BACKGROUND
Malignant 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 (Desjardins et 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.
METHODS
We 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.
RESULTS
PVSRIPO 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.
CONCLUSIONS
Our 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.
背景
恶性胶质瘤会募集密集的炎症浸润物，其中包括与胶质瘤相关的巨噬细胞和小胶质细胞（GAMM），促进免疫抑制、逃逸和肿瘤进展。与单核吞噬细胞系统中的所有细胞一样，GAMM 持续表达脊髓灰质炎病毒受体 CD155。除了髓样细胞外，CD155 在恶性胶质瘤的肿瘤部位广泛上调。在复发性胶质母细胞瘤患者中，肿瘤内给予高度减毒的 rhino：脊髓灰质炎病毒嵌合体 PVSRIPO 治疗，可产生长期生存和持久的影像学反应（Desjardins 等人，《新英格兰医学杂志》，2018 年）。这种情况引发了关于髓样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。
方法
我们使用盲法、经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，研究了 PVSRIPO 免疫疗法在免疫功能正常的小鼠脑肿瘤模型中的作用。
结果
PVSRIPO 治疗引起了 GAMM 浸润物的强烈参与，伴随着大量但短暂的肿瘤消退。这伴随着肿瘤周围正常大脑中明显的小胶质细胞激活和增殖，在同侧半球延伸到对侧半球。没有恶性细胞裂解感染的证据。PVSRIPO 引发的小胶质细胞激活发生在持续的先天抗病毒炎症的背景下，与 GAMM 上程序性细胞死亡配体 1（PD-L1）免疫检查点的诱导有关。将 PVSRIPO 与 PD1/PD-L1 阻断联合使用可导致持久缓解。
结论
我们的工作表明 GAMM 是 PVSRIPO 诱导的抗肿瘤炎症的积极驱动因素，并揭示了 PVSRIPO 对大脑驻留髓样细胞进行的深刻和广泛的神经炎症激活。
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