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Subclone of resistant CT26 murine tumor shows high sensitivity to VA7 virotherapy: A novel system to study innate immunity and antigen dominance in oncolytic immuno-virotherapy

ABSTRACT: Recently, attenuated Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN) unresponsive human U87 glioma xenografts while IFN responsive mouse GL261 and CT-2A gliomas proved refractory to the oncolytic virotherapy. Here we describe in two clones of a well established Balb/c mouse tumor cell line, CT26 murine colon carcinoma, diametrically opposed IFN responsiveness and sensitivity to oncolytic virus. Both CT26WT and CT26LacZ clones secreted biologically active type I IFN in vitro upon infection but virus replication was self-limiting only in CT26WT cells. Total transcriptome sequencing (RNA-Seq) and western blotting experiments revealed that in sharp contrast to CT26LacZ cells, CT26WT cells had strong constitutive expression of 56 different genes associated with pattern recognition and type I interferon signaling pathways, spanning two reported anti-RNA virus gene signatures and22 genes that have been reported to have direct anti-Alphaviral activity. Correspondingly, only CT26LacZ tumors were infectable in vivo, resulting in rapid central necrosis of the  tumors by 96 hours post infection and complete tumor eradication both in immunocompetent and in SCID mice. CT26LacZ tumor eradication by oncolysis induced 100% protective immunity against homologous CT26LacZ challenge but only 50% protection against heterologous CT26WT challenge, indicating LacZ immune dominance over shared antigens. We believe the two clone CT26 system  described herein constitutes a challenging yet realistic model for clonally and immunologically heterogeneous cancer where a strong therapy efficacy bias toward sensitive tumor subpopulations might falsely predict therapeutic success on a broad patient scale highlighting the necessity of successful pre-screening for responsive tumors. RNA-Seq in CT26 tumor cell line

ORGANISM(S): Mus musculus  

SUBMITTER: Janne Ruosalainen   Minna U Kaikkonen 

PROVIDER: E-GEOD-53001 | ArrayExpress | 2014-09-05



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Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model.

Ruotsalainen J J JJ   Kaikkonen M U MU   Niittykoski M M   Martikainen M W MW   Lemay C G CG   Cox J J   De Silva N S NS   Kus A A   Falls T J TJ   Diallo J-S JS   Le Boeuf F F   Bell J C JC   Ylä-Herttuala S S   Hinkkanen A E AE   Vähä-Koskela M J MJ  

Gene therapy 20140918 1

In our earlier studies, Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN-I)-unresponsive human U87-luc glioma xenografts, whereas interferon-responsive mouse gliomas proved refractory. Here, we describe in two clones of CT26 murine colon carcinoma, opposed patterns of IFN-I responsiveness and sensitivity to VA7. Both CT26WT and CT26LacZ clones secreted biologically active interferon in vitro upon virus infection but only CT26WT cells were protected. Focal infection of  ...[more]

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