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

Autor:	Marotte L; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Simon S; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Vignard V; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Dupre E; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Gantier M; LabEx IGO, Université de Nantes, Nantes, France.; Université de Nantes, Inserm, CRTI, F-44000 Nantes, France., Cruard J; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Alberge JB; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France., Hussong M; NGS Assay Research & Development, Qiagen Sciences, Frederick, Maryland, United States., Deleine C; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Heslan JM; LabEx IGO, Université de Nantes, Nantes, France.; Université de Nantes, Inserm, CRTI, F-44000 Nantes, France., Shaffer J; NGS Assay Research & Development, Qiagen Sciences, Frederick, Maryland, United States., Beauvais T; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Gaschet J; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Scotet E; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Fradin D; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Jarry A; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France.; LabEx IGO, Université de Nantes, Nantes, France., Nguyen T; Université de Nantes, Inserm, CRTI, F-44000 Nantes, France., Labarriere N; Université de Nantes, Inserm, CRCINA, F-44000 Nantes, France Nathalie.Labarriere@univ-nantes.fr.; LabEx IGO, Université de Nantes, Nantes, France.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Jan; Vol. 8 (1).
DOI:	10.1136/jitc-2019-000311
Abstrakt:	Background: Genome editing offers unique perspectives for optimizing the functional properties of T cells for adoptive cell transfer purposes. So far, PDCD1 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. Methods: Here we used the transfection of CAS9/sgRNA ribonucleoproteic complexes to edit PDCD1 gene in human effector memory CD8 + T cells specific for the melanoma antigen Melan-A. We cloned edited T cell populations and validated PDCD1 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. Results: Here we demonstrated the feasibility to edit PDCD1 gene in human effector memory melanoma-specific T lymphocytes. We showed that PD-1 expression was dramatically reduced or totally absent on PDCD1 -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. Conclusion: 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. Competing Interests: Competing interests: The authors declare that JS and MH are employed by Qiagen; however, the research was conducted in the absence of any potential conflict of interest. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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