Blocking feedback immunosuppression of antigen presentation in brain tumor during oncolytic virotherapy with oHSV-mshPKR.

IF 5.3 2区 医学 Q1 ONCOLOGY
Nobushige Tsuboi, Kimberly A Rivera-Caraballo, Upasana Sahu, Rafal Pacholczyk, Eugene Douglass, Theodore S Johnson, Qin Wang, Ravindra Kolhe, Catherine C Hedrick, David H Munn, Bangxing Hong
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引用次数: 0

Abstract

Glioblastoma (GBM) is the most frequent malignant brain tumor. We recently discovered that oncolytic herpes simplex virus engineered to disable tumor-intrinsic protein kinase R (PKR) signaling (oHSV-shPKR) could increase oHSV oncolysis and anti-tumor immune response. However, here we show that disabling tumor-intrinsic PKR signaling can also induce the activation of the indoleamine 2,3-dioxygenase (IDO) signaling pathway. Both GBM tumor progression and oHSV intratumoral therapy increased infiltration of IDO+CD11c+ dendritic cells into the tumor. The coculture of oHSV-infected human GBM neurospheres with monocytes-derived dendritic cells (MoDCs) dramatically increased IDO signaling activation in MoDCs through type-I interferon signaling. Addition of IDO inhibitor (indoximod) in the coculture significantly increased MoDCs activation and reduced the consumption of tryptophan. Combining indoximod and oHSV significantly inhibited tumor growth, and induced antigen specific CD8+ T cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of glioblastoma.

oHSV-mshPKR溶瘤病毒治疗中对脑肿瘤抗原呈递的阻断反馈免疫抑制
胶质母细胞瘤是最常见的恶性脑肿瘤。我们最近发现,溶瘤性单纯疱疹病毒(oHSV- shpkr)被设计成使肿瘤内在蛋白激酶R (PKR)信号失活,可以增加oHSV的溶瘤和抗肿瘤免疫反应。然而,我们在这里表明,禁用肿瘤内在的PKR信号也可以诱导吲哚胺2,3-双加氧酶(IDO)信号通路的激活。GBM肿瘤进展和oHSV肿瘤内治疗均增加IDO+CD11c+树突状细胞向肿瘤的浸润。ohsv感染的人GBM神经球与单核细胞来源的树突状细胞(MoDCs)共培养,通过i型干扰素信号传导显著增加MoDCs中IDO信号的激活。在共培养中添加IDO抑制剂(indoximod)显著增加了modc的激活并减少了色氨酸的消耗。indoximod与oHSV联合使用可显著抑制肿瘤生长,诱导抗原特异性CD8+ T细胞活化。这些结果表明,在胶质母细胞瘤溶瘤病毒治疗过程中,IDO通路的抑制可以显著阻断反馈免疫抑制。
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来源期刊
CiteScore
11.20
自引率
1.80%
发文量
331
审稿时长
3 months
期刊介绍: Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
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