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Strong antigen-specific T-cell immunity induced by a recombinant human TERT measles virus vaccine and amplified by a DNA/viral vector prime boost in IFNAR/CD46 mice

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Abstract

Cancer immunotherapy is seeing an increasing focus on vaccination with tumor-associated antigens (TAAs). Human telomerase (hTERT) is a TAA expressed by most tumors to overcome telomere shortening. Tolerance to hTERT can be easily broken both naturally and experimentally and hTERT DNA vaccine candidates have been introduced in clinical trials. DNA prime/boost strategies have been widely developed to immunize efficiently against infectious diseases. We explored the use of a recombinant measles virus (MV) hTERT vector to boost DNA priming as recombinant live attenuated measles virus has an impressive safety and efficacy record. Here, we show that a MV-TERT vector can rapidly and strongly boost DNA hTERT priming in MV susceptible IFNAR/CD46 mouse models. The cellular immune responses were Th1 polarized. No humoral responses were elicited. The 4 kb hTERT transgene did not impact MV replication or induction of cell-mediated responses. These findings validate the MV-TERT vector to boost cell-mediated responses following DNA priming in humans.

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Abbreviations

AP:

Alkaline phosphatase

ATU:

Additional transcription unit

BCIP:

5-Bromo-4-chloro-3-indolyl phosphate

CBA:

Cytometric beads array

MOI:

Multiplicity of infection

MV:

Measle virus

NBT:

Nitro blue tetrazolium chloride

PVDF:

Polyvinylidene fluoride

ROI:

Region of interest

Tg:

Transgenic

TMB:

3,3′,5,5′-Tetramethylbenzidine

Ubi:

Ubiquitin

UCP:

Universal cancer peptide

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Acknowledgements

The authors would like to thank Ludovic Bourré, Anne-Sophie Pailhes-Jimenez, Emanuèle Bourges, Rahima Youssi and Pascal Clayette for experimental and editorial help, and the staff of the Institut Pasteur’s animal facilities and imaging platform. Funding was provided by Association Nationale de la Recherche et de la Technologie (Grant no. 2012/0152).

Funding

We would like to thank Shannon A. Fairbanks and Bernardo Fort Brescia for their unswerving support. Elodie Pliquet was supported by an industrial Ph.D. fellowship from the French National Association of Research and Technology (ANRT).

Author information

Authors and Affiliations

  1. Invectys, Pépinière Paris Santé Cochin, 27, rue du Faubourg Saint Jacques, 75014, Paris, France

    Elodie Pliquet, Marie Escande, Jessie Thalmensi, Thomas Bestetti, Marion Julithe, Christelle Liard, Thierry Huet, Simon Wain-Hobson & Pierre Langlade-Demoyen

  2. Molecular Retrovirology Unit, Institut Pasteur, CNRS-URA 3015, Paris, France

    Elodie Pliquet, Simon Wain-Hobson & Pierre Langlade-Demoyen

  3. Viral Genomics and Vaccination Unit, Institut Pasteur, CNRS-UMR 3965, Paris, France

    Claude Ruffie, Valérie Najburg, Chantal Combredet & Frédéric Tangy

Authors
  1. Elodie Pliquet
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  2. Claude Ruffie
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  3. Marie Escande
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  4. Jessie Thalmensi
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Contributions

SW-H, FT and PL-D conceived the project. They also shared their knowledge and experience to help EP with the experimental program design. EP performed and analyzed the experiments under the supervision of CL and TH. EP and CR carried out mice experiments. VN and CC constructed the recombinant measles telomerase virus. ME, JT, TB and MJ provided technical help. EP analysed all the data and wrote the manuscript together with SW-H and FT. All authors viewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Elodie Pliquet.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

All protocols have been submitted and approved by the Pasteur Institute office of laboratory animal care CETEA no. 89 under the references 2013-0026 on February 01st, 2013 and 2014-0061 on October 07th, 2015 and by French Committee for Hygiene, Safety and Working Conditions (CHSCT) under the reference 07.157 on April 10th, 2007 and 16.0013 on January 8th, 2016. All in vivo experiments were conducted in strict accordance with good animal practice and complied with local animal experimentation and ethics committee guidelines of the Pasteur Institute (agreement no. 75-15-01 delivered on the 06th September 2013 and no. A75-15-01-1 on 18th August 2014) and Directive 2010/63/EU on the harmonization of laws, regulations and administrative provisions relating to the protection of animals.

Animal source

IFNAR/CD46 (IFN-α/βR−/− CD46+/−) mouse strain used for immunization experiments was generated by Frédéric Tangy’s team by cross-breeding and backcross between FVB/CD46+/− mice (gift from F. Grosveld, Erasmus University, Rotterdam, The Netherlands) and 129sv IFN-α/βR−/− mice which lack the type I IFN receptor (gift from M. Aguet, Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland). HHD/IFNAR/CD46 (HHD+/+ CD46+/− IFN-α/βR−/−) mouse strain was generated by Frédéric Tangy’s team by cross-breeding and backcross between HHD mice (human β2m–HLA-A2.1 α1α2-H-2Dbα3-transmembrane and H-2Db−/−β2mb−/− double knockout; mice generated at Pasteur Institute by François Lemonnier) and IFNAR/CD46 mice.

Cell line authentication

HEK-293-T7-MV cell line was produced, provided and patented by Frédéric Tangy and the Institut Pasteur. Vero cells were provided by the American Type Culture Collection (ATCC®) under reference number CCL-81™.

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Pliquet, E., Ruffie, C., Escande, M. et al. Strong antigen-specific T-cell immunity induced by a recombinant human TERT measles virus vaccine and amplified by a DNA/viral vector prime boost in IFNAR/CD46 mice. Cancer Immunol Immunother 68, 533–544 (2019). https://doi.org/10.1007/s00262-018-2272-3

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