In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1558-1558
Abstract:
Innovative biotherapeutic approaches for experimental malignant gliomas (MGs) and brain tumor stem cells (BTSCs) include using oncolytic viruses such as Myxoma Virus (Myxv) or immune cells such as Natural Killer (NK) cells. In this study, we combined the individual strengths of using NK cells and Myxv to treat MGs with a view of overcoming the potential limitations posed when each is used as monotherapy. All MGs (U87, U251) and BTSCs (25EF and 48EF) investigated expressed varying levels of NK ligands including inhibitory MHC-I, activating ULBP1-3, MICA/B, and co-activating nectin-2, poliovirus receptor. Infection of MGs and BTSCs with Myxv resulted in the downregulation of MHC-I expression both on the cell surface and intracellularly. No effect was observed on the expression of NK activating ligands except for the downregulation of nectin-2. The downregulation of MHC-I and nectin-2 by Myxv was specifically mediated by M153 gene of Myxv as loss of M153 restored MHC-I and nectin-2 expression. Subsequently, NK cell degranulation and killing of MGs was enhanced in Myxv-infected cells. Loss of M153 inhibited NK degranulation and lysis of MGs. In vivo, using luciferase-expressing U87 cells in a mouse intracranial model, Myxv accelerated tumor size reduction/clearance by NK cell lysis. Combined intratumoral treatment with Myxv and NK of established U87 tumor accelerated tumor clearance when compared with single treatment with Myxv or NK. Tumor in 66% of mice (4 out of 6 mice) were cleared or significantly reduced within 14 days following combination treatment with Myxv and NK. No significant effect was observed in Myxv or NK singly-treated mice within the same time frame. Clearance of tumors was only first observed in 50% (2 out of 4) of Myxv-treated mice after 25 days Myxv treatment. In NK treated mice, the tumor size rather increased. The enhanced tumor clearance in the combined Myxv and NK treated mice was possibly due to the down-regulation of MHC-I by Myxv since combined treatment with NK cells and mutant Myxv (gene M153 which is responsible for MHC-I down-regulation was deleted) did not result in clearance of tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1558. doi:1538-7445.AM2012-1558
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-1558
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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