Duke University, Durham, NC, USA.
Department of Pathology, Duke University, Durham, NC, USA.
Clin Transl Oncol. 2023 Mar;25(3):696-705. doi: 10.1007/s12094-022-02975-9. Epub 2022 Oct 27.
Medulloblastoma is the most common pediatric malignant brain tumor, consisting of four molecular subgroups (WNT, SHH, Group 3, Group 4) and 12 subtypes. Expression of the cell surface poliovirus receptor (PVR), CD155, is necessary for entry of the viral immunotherapeutic agent, PVSRIPO, a polio:rhinovirus chimera. CD155, physiologically expressed in the mononuclear phagocytic system, is widely expressed ectopically in solid tumors. The objective of this study is to elucidate CD155 expression as both a receptor for PVSRIPO and a therapeutic target in medulloblastoma.
PVR mRNA expression was determined in several patient cohorts and human medulloblastoma cell lines. Patient samples were also analyzed for CD155 expression using immunohistochemistry and cell lines were analyzed using Western Blots. CD155 was blocked using a monoclonal antibody and cell viability, invasion, and migration were assessed.
PVR mRNA expression was highest in the WNT subgroup and lowest in Group 4. PVR expression in the subgroups of medulloblastoma were similar to other pediatric brain and non-brain tumors. PVR expression was largely not associated with subgroup or subtype. Neither PVR protein expression intensity nor frequency were associated with overall survival. PVR expression was elevated in Group 3 patients with metastases but there was no difference in paired primary and metastatic medulloblastoma. Blocking PVR resulted in dose-dependent cell death, decreased invasion in vitro, and modestly inhibited cell migration.
CD155 is expressed across medulloblastoma subgroups and subtypes. Blocking CD155 results in cell death and decreased cellular invasion. This study provides rationale for CD155-targeting agents including PVSRIPO and antibody-mediated blockade of CD155.
髓母细胞瘤是最常见的小儿脑恶性肿瘤，由四个分子亚群（WNT、SHH、Group 3、Group 4）和 12 个亚型组成。细胞表面脊髓灰质炎病毒受体（PVR）、CD155 的表达对于病毒免疫治疗剂 PVSRIPO 的进入是必要的，PVSRIPO 是一种脊髓灰质炎病毒：鼻病毒嵌合体。CD155 在单核吞噬细胞系统中生理性表达，在实体瘤中广泛异位表达。本研究的目的是阐明 CD155 作为 PVSRIPO 的受体和髓母细胞瘤治疗靶点的表达。
在几个患者队列和人髓母细胞瘤细胞系中确定 PVR mRNA 表达。使用免疫组织化学和 Western Blots 分析患者样本中的 CD155 表达，并用单克隆抗体阻断 CD155，评估细胞活力、侵袭和迁移。
WNT 亚组的 PVR mRNA 表达最高，Group 4 最低。髓母细胞瘤各亚组的 PVR 表达与其他小儿脑肿瘤和非脑肿瘤相似。PVR 表达与亚组或亚型均无关联。PVR 蛋白表达强度或频率均与总生存期无关。转移的 Group 3 患者的 PVR 表达升高，但配对的原发和转移性髓母细胞瘤无差异。阻断 PVR 导致剂量依赖性的细胞死亡、体外侵袭减少，并适度抑制细胞迁移。
CD155 在髓母细胞瘤各亚组和亚型中表达。阻断 CD155 导致细胞死亡和细胞侵袭减少。本研究为 CD155 靶向药物提供了依据，包括 PVSRIPO 和 CD155 抗体的阻断。
