ИСТИНА

Oncolytic viruses represent a new class of anticancer drugs [1]. These are naturally occurring non-pathogenic viruses and their derivatives modified by genetic engineering or bioselection to increase safety and enhance oncolytic properties [2]. The action of oncolytic viruses is based on their ability to selectively destroy tumor cells without affecting normal tissues and organs. These cells have selective sensitivity to viruses due to disruption of tissue architecture inside the tumor, increased permeability of tumor vessels, and frequent disturbances in interferon induction systems [3]. Multiple viruses of different families have demonstrated oncolytic properties and are considered as platforms for the development of oncoselective strains. Enteroviruses, a large family of small viruses containing single-stranded positive-sense RNA genome, are also promising candidates [5]. However, the effectiveness of their effects on different tumors is not completely predictable, which complicates their practical use. In this regard, molecular determinants of cancer cell sensitivity to enteroviruses need to be investigated [6-9]. In order to identify new markers of sensitivity for enterovirus infection, a knockout HEK293T cells were obtained using transduction by the pooled GeCKO 2 lentivirus libraries (Genome- Scale CRISPR Knock-Out) and infected with Echo1 Farouk strain, an oncolytic virus [11], at moi=1.The survived cell clones grew as colonies and were subcultured, followed by determination of the knocked out genes. In two sublines, a disruption of the FCGRT gene encoding neonatal Fc receptor (FcRn) was found. The FcRn was recently identified as an entry receptor for some human echoviruses [10]. The obtained cells were tested for sensitivity to various enterovirus strains: Echo1 (Farouk), Echo7, Echo11, Echo12 (Travis), Echo30, vaccine polioviruses types 1, 2, 3 (Sabin), nonpathogenic Coxsackie virus A7 and B5. We found that the FCGRT knockout resulted in a reduced sensitivity to Coxsackie A7 and Echo11, or the complete loss of sensitivity to Echo1, Echo7, and Echo12. The work was supported by the Russian Science Foundation (grant no. 20-14-00178 and no. 20-75-10157). ----------- References --------------- (1) Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: A new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14(9). doi:10.1038/nrd4663 (2) Bell JC, McFadden G. Editorial overview: Oncolytic viruses - Replicating virus therapeutics for the treatment of cancer. Curr Opin Virol. 2015;13. doi:10.1016/j.coviro.2015.07.005 (3) Matveeva O V., Guo ZS, Shabalina SA, Chumakov PM. Oncolysis by paramyxoviruses: Multiple mechanisms contribute to therapeutic efficiency. Mol Ther - Oncolytics. 2015;2. doi:10.1038/mto.2015.11 (4) Maroun J, Mu˜noz-Al´ıa M, Ammayappan A, Schulze A, Peng KW, Russell S. Designing and building oncolytic viruses. Future Virol. 2017;12(4). doi:10.2217/fvl-2016-0129 (5) Annels NE, Arif M, Simpson GR, et al. Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus. Mol Ther - Oncolytics. 2018;9. doi:10.1016/j.omto.2018.02.001 (6) Goetz C, Gromeier M. Preparing an oncolytic poliovirus recombinant for clinical application against glioblastoma multiforme. Cytokine Growth Factor Rev. 2010;21(2- 3). doi:10.1016/j.cytogfr.2010.02.005 (7) Annels NE, Mansfield D, Arif M, et al. Phase I trial of an ICAM-1-targeted immunotherapeutic-coxsackievirus A21 (CVA21) as an oncolytic agent against non muscle-invasive bladder cancer. Clin Cancer Res. 2019;25(19). doi:10.1158/1078- 0432.CCR-18-4022 (8) Alberts P, Tilgase A, Rasa A, Bandere K, Venskus D. The advent of oncolytic virotherapy in oncology: The Rigvir R○ story. Eur J Pharmacol. 2018;837. doi:10.1016/j.ejphar.2018.08.042 (9) Shafren DR. Viral Cell Entry Induced by Cross-Linked Decay-Accelerating Factor. J Virol. 1998;72(11). doi:10.1128/jvi.72.11.9407-9412.1998 (10) Zhao X, Zhang G, Liu S, Chen X, Peng R, Dai L, Qu X, Li S, Song H, Gao Z, Yuan P, Liu Z, Li C, Shang Z, Li Y, Zhang M, Qi J, Wang H, Du N, Wu Y, Bi Y, Gao S, Shi Y, Yan J, Zhang Y, Xie Z, Wei W, Gao GF. Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B. Cell. 2019 May 30;177(6):1553-1565.e16. doi: 10.1016/j.cell.2019.04.035 (11) J. Yl¨a-Pelto, L. Tripathi, P. Susi Therapeutic Use of Native and Recombinant Enteroviruses Viruses, 8 (2016), p. 57