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
Juris Jansons,
Ekaterina Bayurova,
Dace Skrastina,
Alisa Kurlanda,
Ilze Fridrihsone,
Dmitry Kostyushev,
Anastasia Kostyusheva,
Alexander Artyuhov,
Erdem Dashinimaev,
Darya Avdoshina,
Alla Kondrashova,
Vladimir Valuev-Elliston,
Oleg Latyshev,
Olesja Eliseeva,
Stefan Petkov,
Maxim Abakumov,
Laura Hippe,
Irina Kholodnyuk,
Elizaveta Starodubova,
Tatiana Gorodnicheva,
Alexander Ivanov,
Ilya Gordeychuk,
Maria Isaguliants
Affiliations
Juris Jansons
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
Ekaterina Bayurova
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
Dace Skrastina
Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia
Alisa Kurlanda
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
Ilze Fridrihsone
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
Dmitry Kostyushev
National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia
Anastasia Kostyusheva
National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow 127994, Russia
Alexander Artyuhov
Center for Precision Genome Editing and Genetic Technologies, Pirogov Russian National Research Medical University, Moscow 127994, Russia
Erdem Dashinimaev
Center for Precision Genome Editing and Genetic Technologies, Pirogov Russian National Research Medical University, Moscow 127994, Russia
Darya Avdoshina
Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 127994, Russia
Alla Kondrashova
Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Moscow 127994, Russia
Vladimir Valuev-Elliston
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 127994, Russia
Oleg Latyshev
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
Olesja Eliseeva
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
Stefan Petkov
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
Maxim Abakumov
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
Laura Hippe
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
Irina Kholodnyuk
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
Elizaveta Starodubova
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 127994, Russia
Tatiana Gorodnicheva
Evrogen, Moscow 127994, Russia
Alexander Ivanov
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
Ilya Gordeychuk
N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Moscow 127994, Russia
Maria Isaguliants
Department of Research, and Department of Pathology, Pathology, Rīga Stradiņš University, LV-1007 Riga, Latvia
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.
