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Clonal Variation in Interferon Response Determines the Outcome of Oncolytic Virotherapy in Mouse CT26 Colon Carcinoma Model

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Clonal Variation in Interferon Response Determines the Outcome of Oncolytic Virotherapy in Mouse CT26 Colon Carcinoma Model Gene Therapy (2015) 22,65–75 © 2015 Macmillan Publishers Limited All rights reserved 0969-7128/15 www.nature.com/gt ORIGINAL ARTICLE Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model JJ Ruotsalainen1, MU Kaikkonen1, M Niittykoski1, MW Martikainen1, CG Lemay2, J Cox2, NS De Silva2, A Kus2, TJ Falls2, J-S Diallo2, F Le Boeuf2, JC Bell2, S Ylä-Herttuala1, AE Hinkkanen1 and MJ Vähä-Koskela2 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 CT26WT cultures was self-limiting but could be rescued using IFN-I pathway inhibitor Ruxolitinib or antibody against IFNβ. Whole transcriptome sequencing (RNA-Seq) and protein expression analysis revealed that CT26WT cells constitutively expressed 56 different genes associated with pattern recognition and IFN-I signaling pathways, spanning two reported anti-RNA virus gene signatures and 22 genes with reported anti-alphaviral activity. Whereas CT26WT tumors were strictly virus-resistant in vivo, infection of CT26LacZ tumors resulted in complete tumor eradication in both immunocompetent and severe combined immune deficient mice. In double-flank transplantation experiments, CT26WT tumors grew despite successful eradication of CT26LacZ tumors from the contralateral flank. Tumor growth progressed uninhibited also when CT26LacZ inoculums contained only a small fraction of CT26WT cells, demonstrating dominance of IFN responsiveness when heterogeneous tumors are targeted with interferon-sensitive oncolytic viruses. Gene Therapy (2015) 22, 65–75; doi:10.1038/gt.2014.83; published online 18 September 2014 INTRODUCTION fluorescence marker EGFP to probe defined mixtures of CT26WT Despite the recent advances in modern cancer therapies, and CT26LacZ cells which, as we report here, represent a pair of prognoses of advanced cancers remain poor. Oncolytic virother- IFN-I-responsive and -unresponsive tumor clones, respectively. apy presents an attractive option to chemo-, radio- and Resistance of CT26WT cells to virus spread in vitro was dependent monoclonal antibody therapies, as oncolytic viruses display low on IFN-I and could be overcome by neutralization of secreted β toxicity and may induce strong anti-tumor immune responses.1,2 interferon beta (IFN ) or by interference with intracellular IFN fi Most viruses are sensitive to type I interferon (IFN-I) and many signaling. Oncolytic ef cacy in intradermal CT26WT and CT26LacZ oncolytic viruses replicate more efficiently in tumors displaying tumors in immunocompetent mice was 0 and 100 percent, constitutive Ras-pathway activation, which facilitates oncolytic respectively. Furthermore, we describe here, to our knowledge the fi virus replication by interfering with virus-mediated IFN-I rst time in the context of oncolytic virotherapy, a constitutive induction.3,4 Genes involved in IFN-I signaling are often tran- global antiviral gene signature comprising besides two documen- scriptionally repressed in tumors as they play a role in growth ted anti-RNA virus signatures, the OAS/Mx and immune-related restriction, apoptosis and immunogenicity, and one of the GTPases (IRGs), also several other known anti-alphavirus effectors and IFN-I signal mediators. principal predictive markers for oncolytic virus efficacy is the limited capacity of the tumor to mount antiviral defense in response to IFN-I.5–11 However, although heterogeneity in IFN-I signaling among cell lines and patients is apparent, the RESULTS implications for virotherapy of patient-specific intratumoral Balb/c CT26 colon carcinoma clones differ in their responsiveness heterogeneity have not been studied. It has been unclear whether to IFN-I and susceptibility to infection clonal selection of resistant subpopulations, known to confer Spurred by the contrasting sensitivity of different glioma cells to resistance to other advanced therapies,12 may also hamper oncolytic VA7,17,18 we screened other cancer cell lines in our oncolytic virotherapy, and preclinical models for such phenom- laboratories as part of an effort to identify variables affecting enon have not been described. permissiveness to oncolytic viruses. We discovered that two To address these shortcomings, we have used IFN-I-sensitive clones of CT26 mouse (Balb/c) colon carcinoma cells originally oncolytic Semliki Forest virus (SFV) VA711,13–17 encoding generated in Nicholas Restifo’s laboratory,19 differed in sensitivity 1A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland and 2Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada. Correspondence: Professor AE Hinkkanen, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, Neulaniementie 2, Kuopio 70211, Finland. E-mail: ari.hinkkanen@uef.fi Received 7 March 2014; revised 11 June 2014; accepted 6 August 2014; published online 18 September 2014 Clonal dominance in oncolytic virotherapy JJ Ruotsalainen et al 66 to replication and oncolysis by VA7 both in vitro and in vivo, with equivalents) ISG15, ISG20, Rsad2 (Viperin), Gbp2, Irgm2 (GTPI), the retrovirally transduced CT26LacZ cells displaying greater Igtp, Tgtp1/2, Ifi47 (IRG47), Irgm1 (LRG-47), Iigp1, Rig-I, PKR, IRF7, susceptibility to the virus than the non-transduced CT26WT Ifitm3, MDA5, Gm6907 (Phf11), IRF9, Gbp4, Ifi44l, Ube2l6 and OAS3 counterparts. Specifically, VA7-EGFP replicated in (Figure 1a, have been reported21–25 to have direct anti-alphaviral activity Supplementary Table S1) and killed (Figure 1b) CT26LacZ cells alone or in combination with zinc antiviral protein that was more effectively than CT26WT cells, and intratumoral virus expressed at equal levels in both of the cell lines (Figure 3a, injection resulted in complete eradication of CT26LacZ tumors Table 1). The genes expressed at higher levels in CT26WT cells but had no impact on CT26WT tumor growth (Figure 1c). As our compared with CT26LacZ cells included the central IFN-I signaling previous work with murine gliomas strongly implicated IFN-I- mediators STAT1 and IRF9, and in addition five IRGs constituting a mediated restriction of virus infection, we tested VA7 infectivity recently reported anti-alphaviral gene signature.26 Furthermore, and killing capacity in the presence and absence of IFNβ. we observed constitutive expression of OAS and Mx ISGs, which Experiments revealed robust infection of both cell lines if left have been proposed as a resistance gene signature against untreated, but upon IFNβ pretreatment almost complete inhibi- another IFN-I sensitive virus, VSV.27 tion of virus replication and oncolysis only in the CT26WT cells Interestingly, VA7 infection did not cause statistically significant (Figure 1d). Infectivity of both VA7 and another IFN-I-sensitive transcriptomic changes in CT26WT cells (Figure 3a), not even in virus, vesicular stomatitis virus (VSV), was inhibited by IFNβ in a IFNβ mRNA levels despite that these cells released IFNβ protein dose-dependent manner in CT26WT cells whereas CT26LacZ cells upon prolonged infection (Figure 2b). This might be explained by failed to mount complete antiviral defense even at 10 000 U ml − 1 the early sampling time point (12 h p.i.) we chose to avoid the IFNβ (Supplementary Figure S1). transcriptional shutdown and lysis of sensitive CT26LacZ cells and/ or by the constitutive expression of the antiviral factors listed Both CT26 clones secrete IFNβ but only CT26WT cells are capable above which may reduce the need for de novo transcriptional of effectively transmitting IFNβ-dependent antiviral signaling activation. To further characterize the IFN-I sensitivities of the two clones and to mimic in vivo situation, we used a single-focus expansion Impaired antiviral defense in CT26LacZ cells is associated with low assay20 that restricts virus replication to radial growth beneath an STAT1 levels and may be restored by non-specific transfection agarose overlay in the presence or absence of neutralizing To confirm our transcriptomic findings, we probed by western (polyclonal) antibodies to IFNα or IFNβ. Results revealed that blotting select differentially transcribed IFN-I signaling mediators although VA7 is capable of infecting cells at the inoculation site, it in CT26WT and CT26LacZ cells at multiple time points p.i. or post is nevertheless incapable of spreading radially in CT26WT cells recombinant mIFNβ exposure. As an immediate downstream because of paracrine effects of IFNβ (Figure 2a). Furthermore, we indicator of IFN-I receptor activation we chose STAT1, which found that though CT26LacZ cells did not effectively respond to allows for detection of phosphorylation-dependent activation, and IFN-I, they were able to produce it upon VA7 infection (Figure 2b). as an IFN-I-inducible effector we chose OAS, known to be This interferon was biologically active, as cell culture supernatants upregulated in virus-resistant GL261 gliomas upon VA7 from infected CT26LacZ cells protected CT26WT cells against VA7 infection17 and previously identified as a tumor resistance
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