Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses
Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses
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DOI：
10.1038/s41598-020-61736-2
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发表时间：
2020-03-20
影响因子：
4.6
通讯作者：
Nakashima, Hiroshi
中科院分区：
文献类型：
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作者：
Alayo, Quazim A.;Ito, Hirotaka;Nakashima, Hiroshi
肿瘤溶解病毒(OVS)在癌症治疗中的作用方式被认为依赖于对感染的肿瘤细胞的直接初始细胞毒作用以及随后针对肿瘤的免疫细胞反应的激活。为了在小鼠胶质母细胞瘤(GBM)模型中研究这两种作用，我们使用了结构性表达I型单纯疱疹病毒(HSV1)HSV-1受体Nectin-1的小鼠GBM细胞，以允许更有效地感染和复制溶瘤HSV(OHSV)。这些细胞被进一步用替代肿瘤抗原进行工程改造，以便于T细胞活性的分析。我们利用基于MRI的体积计量学来测量注射OHSV后的GBM反应，并利用生物发光成像(BLI)来确定注射的肿瘤中OHSV的复制动力学。我们发现，在注射OHSV后7天内，替代肿瘤抗原和OHSV抗原特异性CD8+T细胞的浸润增加。表达耗竭标志的肿瘤浸润性CD8+T细胞未见增加，但OHSV感染可导致注射的GBM中PD-1+CD8+T细胞减少，而干扰素-γ+CD8+T细胞增加。OHSV介导的基底膜体积的减少与病毒和肿瘤抗原特异性CD8+T细胞以及OHSV瘤内基因活性的增加有显著的直接相关性。这些发现提示CD8+T细胞对肿瘤和病毒抗原的细胞毒作用以及瘤内OHSV基因的表达在OHSV介导的GBM治疗中具有重要意义。
The mode of action for oncolytic viruses (OVs) in cancer treatment is thought to depend on a direct initial cytotoxic effect against infected tumor cells and subsequent activation of immune cell responses directed against the neoplasm. To study both of these effects in a mouse model of glioblastoma (GBM), we employed murine GBM cells engineered to constitutively express the type I Herpes Simplex Virus (HSV1) HSV-1 receptor, nectin-1, to allow for more efficient infection and replication by oncolytic HSV (oHSV). These cells were further engineered with a surrogate tumor antigen to facilitate assays of T cell activity. We utilized MRI-based volumetrics to measure GBM responses after injection with the oHSV and bioluminescent imaging (BLI) to determine oHSV replicative kinetics in the injected tumor mass. We found increased infiltration of both surrogate tumor antigen- and oHSV antigen-specific CD8+ T cells within 7 days after oHSV injection. There was no increase in tumor infiltrating CD8+ T cells expressing "exhaustion" markers, yet oHSV infection led to a reduction in PD-1+ CD8+ T cells in injected GBMs and an increase in IFN gamma+ CD8+ T cells. There was a significant direct correlation between oHSV-mediated reduction in GBM volume and increased infiltration of both viral and tumor antigen-specific CD8+ T cells, as well as oHSV intratumoral gene activity. These findings imply that CD8+ T cell cytotoxicity against both tumor and viral antigens as well as intratumoral oHSV gene expression are important in oHSV-mediated GBM therapy.