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Expression of the Reverse Transcriptase Domain of Telomerase Reverse Transcriptase Induces Lytic Cellular Response in DNA-Immunized Mice and Limits Tumorigenic and Metastatic Potential of Murine Adenocarcinoma 4T1 Cells

1
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
2
Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia
3
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
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Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 127994, Russia
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National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia
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Center for Precision Genome Editing and Genetic Technologies, Pirogov Russian National Research Medical University, Moscow 127994, Russia
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Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 127994, Russia
8
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 127994, Russia
9
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
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Laboratory of Biomedical Nanomaterials, National University of Science and Technology MISIS, Moscow 127994, Russia
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Department of Medical Nanobiotechnologies, Pirogov Russian National Research Medical University, Moscow 127994, Russia
12
Evrogen, Moscow 127994, Russia
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Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow 127994, Russia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Vaccines 2020, 8(2), 318; https://doi.org/10.3390/vaccines8020318
Received: 27 May 2020 / Revised: 14 June 2020 / Accepted: 15 June 2020 / Published: 18 June 2020
(This article belongs to the Special Issue Cancer Immunotherapy: Advances and Future Prospects)
Telomerase reverse transcriptase (TERT) is a classic tumor-associated antigen overexpressed in majority of tumors. Several TERT-based cancer vaccines are currently in clinical trials, but immune correlates of their antitumor activity remain largely unknown. Here, we characterized fine specificity and lytic potential of immune response against rat TERT in mice. BALB/c mice were primed with plasmids encoding expression-optimized hemagglutinin-tagged or nontagged TERT or empty vector and boosted with same DNA mixed with plasmid encoding firefly luciferase (Luc DNA). Injections were followed by electroporation. Photon emission from booster sites was assessed by in vivo bioluminescent imaging. Two weeks post boost, mice were sacrificed and assessed for IFN-γ, interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α) production by T-cells upon their stimulation with TERT peptides and for anti-TERT antibodies. All TERT DNA-immunized mice developed cellular and antibody response against epitopes at the N-terminus and reverse transcriptase domain (rtTERT) of TERT. Photon emission from mice boosted with TERT/TERT-HA+Luc DNA was 100 times lower than from vector+Luc DNA-boosted controls. Bioluminescence loss correlated with percent of IFN-γ/IL-2/TNF-α producing CD8+ and CD4+ T-cells specific to rtTERT, indicating immune clearance of TERT/Luc-coexpressing cells. We made murine adenocarcinoma 4T1luc2 cells to express rtTERT by lentiviral transduction. Expression of rtTERT significantly reduced the capacity of 4T1luc2 to form tumors and metastasize in mice, while not affecting in vitro growth. Mice which rejected the tumors developed T-cell response against rtTERT and low/no response to the autoepitope of TERT. This advances rtTERT as key component of TERT-based therapeutic vaccines against cancer. View Full-Text
Keywords: therapeutic cancer vaccines; telomerase reverse transcriptase (TERT); reverse transcriptase domain; intradermal DNA immunization; electroporation; epitopes; CD4+ and CD8+ lytic T cell response; antibodies; murine adenocarcinoma cells; lentiviral transduction; tumor growth; suppression; rejection; metastasis therapeutic cancer vaccines; telomerase reverse transcriptase (TERT); reverse transcriptase domain; intradermal DNA immunization; electroporation; epitopes; CD4+ and CD8+ lytic T cell response; antibodies; murine adenocarcinoma cells; lentiviral transduction; tumor growth; suppression; rejection; metastasis
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Jansons, J.; Bayurova, E.; Skrastina, D.; Kurlanda, A.; Fridrihsone, I.; Kostyushev, D.; Kostyusheva, A.; Artyuhov, A.; Dashinimaev, E.; Avdoshina, D.; Kondrashova, A.; Valuev-Elliston, V.; Latyshev, O.; Eliseeva, O.; Petkov, S.; Abakumov, M.; Hippe, L.; Kholodnyuk, I.; Starodubova, E.; Gorodnicheva, T.; Ivanov, A.; Gordeychuk, I.; Isaguliants, M. Expression of the Reverse Transcriptase Domain of Telomerase Reverse Transcriptase Induces Lytic Cellular Response in DNA-Immunized Mice and Limits Tumorigenic and Metastatic Potential of Murine Adenocarcinoma 4T1 Cells. Vaccines 2020, 8, 318.

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