Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic T‐lymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTL‐TCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with off‐target specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/β chains, along with CD3 subunits, enables the functional expression of an antigen‐specific TCR complex on NK cell lines NK‐92 and YTS, demonstrated by using a TCR against the HLA‐A2‐restricted tyrosinase‐derived melanoma epitope, Tyr368‐377. Most importantly, the introduction of a TCR complex to NK cell lines enables MHC‐restricted, antigen‐specific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of “mispairing” in TCR gene therapy.
This study focuses on photocatalytic syntheses, in which transition metal ions (Co2+, Fe2+, or Ni2+), as the hole scavengers and surface modifiers of partially reduced graphene oxide, PRGO, were utilized to photoreduce Pt4+. A pulsed UV reactor was used to illuminate the precursors. The electrostatic interaction between the metal ions (Co2+, Fe2+, or Ni2+) and the oxygen functional groups on PRGO was the main parameter, proposed to be the reason controlling Pt4+ reduction and Pt structure and activity. The alternative assumption in managing the oxidation states of Pt was the variation in the oxidation rates of hole scavengers. Pt electrocatalysts’ structural and electrochemical characteristics revealed that utilizing the cobalt-based hole scavenger caused a dominant growth phase of Pt particles at preferred positions on PRGO, with metallic states and improved electrocatalytic activities (ECSA value of 191 m2·g–1 for Co2+ vs 141 m2·g–1 and 127 m2·g–1 for Fe2+ and Ni2+, respectively). Density functional theory (DFT) calculation, on the other hand, suggested that the greater affinity of cobalt and iron ions to oxygen groups could detach more “O” from the graphene plane. Based on the DFT results, less “O” groups in the vicinity of Pt particles gave an amorphous morphology to Pt and facilitated the hydrogen oxidation reaction (HOR).
Introduction of chimeric antigen receptors (CARs) to natural killer (NK) cells has so far been the only practical method for specific targeting of NK cells against surface antigens. In contrast, T-cell receptor (TCR) gene therapy can supply large populations of cytotoxic T-lymphocytes (CTL) genetically modified to express a TCR that can also target intracellular antigens. However, the mispairing of endogenous and genetically transferred TCR subunits constitutes a bottleneck in the development of safe therapies as it often leads to formation of TCRs with unknown specificity. In order to overcome this obstacle and enable intracellular antigen targeting, we propose the use of NK cells for TCR gene therapy. In this study, we approach the obstacles associated with TCR gene therapy from a unique perspective that results in MHC-I-restricted epitope-specific targeting of tumors cells through expression of a functional TCR complex on NK cells. Our results show that the ectopic expression of CD3δ, CD3γ, and CD3ϵ chains along with TCR α/β gene delivery to NK cells enables the functional expression of a TCR specific to the HLA-A2-restiricted tyrosinase-derived melanoma epitope, Tyr368-379. NK cells expressing a functional TCR exhibit the capacity to degranulate in an antigen-specific manner in response to engagement of the cognate peptide/MHC ligand on target cells. In addition, upon engagement of their TCR, NK cells are fully capable of producing proinflammatory cytokines IFNγ and TNF-α, a signature mark of NK cell activation and immune cell recruitment. Finally, NK-TCR cells exhibit MHC-I-restricted antigen detection and antigen-specific lysis of tumor cells both in vitro and in vivo. Antigen-specific targeting of NK cells via TCR gene delivery stands out as a unique discovery providing a novel tool in the field of adoptive immunotherapy that can also overcome the major hurdle of “mispairing” in TCR gene therapy. Clinical trials using NK cells, including genetically modified NK cells expressing activating receptors or CARs, have clearly demonstrated a significant benefit in patients with various malignancies. The overall safety profile and promising clinical benefits of NK cells combined with the exclusive antigen specificity of the TCR, all together provide a novel approach in the design of efficient antigen-specific adoptive immunotherapy. Citation Format: Ayhan Parlar, Ece C. Sayitoglu, Cevriye Pamukcu, Anna-Maria Georgoudaki, Didem Ozkazanc, Mertkaya Aras, Benjamin Josey, Michael Chrobok, Suzanne Branecki, Pegah Zahedimaram, Lolai Ikromzoda, Evren Alici, Batu Erman, Tolga Sutlu, Adil D. Duru. Engineering antigen-specific natural killer cells against the melanoma-associated antigen tyrosinase via TCR gene transfer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A21.
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