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Marotte, Lucine; Simon, Sylvain; Vignard, Virginie; Dupre, Emilie; Gantier, Malika; Cruard, Jonathan; Alberge, Jean-Baptiste; Hussong, Melanie; Deleine, Cecile; Heslan, Jean-Marie; Shaffer, Jonathan; Beauvais, Tiffany; Gaschet, Joelle; Scotet, Emmanuel; Fradin, Delphine; Jarry, Anne; Nguyen, Tuan; Labarriere, Nathalie

Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes

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  • Medientyp: E-Artikel
  • Titel: Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes
  • Beteiligte: Marotte, Lucine; Simon, Sylvain; Vignard, Virginie; Dupre, Emilie; Gantier, Malika; Cruard, Jonathan; Alberge, Jean-Baptiste; Hussong, Melanie; Deleine, Cecile; Heslan, Jean-Marie; Shaffer, Jonathan; Beauvais, Tiffany; Gaschet, Joelle; Scotet, Emmanuel; Fradin, Delphine; Jarry, Anne; Nguyen, Tuan; Labarriere, Nathalie
  • Erschienen: BMJ, 2020
  • Erschienen in: Journal for ImmunoTherapy of Cancer
  • Sprache: Englisch
  • DOI: 10.1136/jitc-2019-000311
  • ISSN: 2051-1426
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Background</jats:title><jats:p>Genome editing offers unique perspectives for optimizing the functional properties of T cells for adoptive cell transfer purposes. So far,<jats:italic>PDCD1</jats:italic>editing has been successfully tested mainly in chimeric antigen receptor T (CAR-T) cells and human primary T cells. Nonetheless, for patients with solid tumors, the adoptive transfer of effector memory T cells specific for tumor antigens remains a relevant option, and the use of high avidity T cells deficient for programmed cell death-1 (PD-1) expression is susceptible to improve the therapeutic benefit of these treatments.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Here we used the transfection of CAS9/sgRNA ribonucleoproteic complexes to edit<jats:italic>PDCD1</jats:italic>gene in human effector memory CD8<jats:sup>+</jats:sup>T cells specific for the melanoma antigen Melan-A. We cloned edited T cell populations and validated<jats:italic>PDCD1</jats:italic>editing through sequencing and cytometry in each T cell clone, together with T-cell receptor (TCR) chain’s sequencing. We also performed whole transcriptomic analyses on wild-type (WT) and edited T cell clones. Finally, we documented in vitro and in vivo through adoptive transfer in NOD scid gamma (NSG) mice, the antitumor properties of WT and PD-1KO T cell clones, expressing the same TCR.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Here we demonstrated the feasibility to edit<jats:italic>PDCD1</jats:italic>gene in human effector memory melanoma-specific T lymphocytes. We showed that PD-1 expression was dramatically reduced or totally absent on<jats:italic>PDCD1</jats:italic>-edited T cell clones. Extensive characterization of a panel of T cell clones expressing the same TCR and exhibiting similar functional avidity demonstrated superior antitumor reactivity against a PD-L1 expressing melanoma cell line. Transcriptomic analysis revealed a downregulation of genes involved in proliferation and DNA replication in PD-1-deficient T cell clones, whereas genes involved in metabolism and cell signaling were upregulated. Finally, we documented the superior ability of PD-1-deficient T cells to significantly delay the growth of a PD-L1 expressing human melanoma tumor in an NSG mouse model.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The use of such lymphocytes for adoptive cell transfer purposes, associated with other approaches modulating the tumor microenvironment, would be a promising alternative to improve immunotherapy efficacy in solid tumors.</jats:p></jats:sec>
  • Zugangsstatus: Freier Zugang