Author: Tin, Enoch ; Khatri, Ismat ; Fang, Karen ; Zhang, Li ; Rutella, Sergio ; Na, Yoosu ; Nawata, Michele ; Lee, Jongbok ; Arteaga, Juan ; Minden, Mark D

BackgroundAllogeneic double-negative T-cell (DNT) therapy has emerged as a novel, off-the-shelf cellular treatment with clinical feasibility, safety, and promising efficacy against leukemia. However, the biology of DNTs is less well characterized, and how DNT therapy distinguishes from conventional γδ T-cell therapy remains unclear. Collectively, this hinders our ability to bolster DNT functionalities in cancer therapy. Here, we performed single-cell RNA sequencing with in vitro and in vivo functional analysis on DNTs. As a significant proportion of DNTs express Vγ9Vδ2 (Vδ2) TCR chain, we compared DNTs with donor-matched conventional Vδ2 T cells expanded with zoledronic acid.MethodsHealthy donor-derived allogeneic DNTs and Vδ2 T cells were expanded ex vivo. Single-cell RNA sequencing analysis was performed on both cellular products to identify the transcriptional landscape and inferred cellular interactions within DNTs, followed by comparisons with donor-matched Vδ2 T cells. Unique cellular subsets found only in DNTs were depleted to identify their contributions to the overall efficacy of DNTs against acute myeloid leukemia. The anti-leukemic activity and in vivo persistence of DNTs and Vδ2 T-cells were explored using flow cytometry-based cytotoxicity assays, memory phenotyping, and xenograft models.ResultsDespite a shared Vδ2 expression between cellular products, we identified unique cellular compositions in DNTs that contribute to distinct transcriptional and cellular communication patterns relative to the donor-matched Vδ2 T cells, including higher expression of genes identified in chimeric antigen receptor T cells that persist in patients with durable cancer-remission. Vδ2–DNTs exhibited strong persistence characteristics, and their presence promoted the cytotoxic capabilities of Vδ2+DNTs in repeated stimulation assays. This unique genetic signature and diverse cellular composition of DNTs resulted in better overall ex vivo expansion, prolonged persistence, and superior anti-leukemic activity compared with Vδ2 T cells in vitro and in vivo.ConclusionsThese results highlight the unique transcriptional, cellular, and functional profile of human DNTs and support the continued clinical investigation of allogeneic DNT therapy. The data also provide a reference gene signature that may help improve the efficacy of other types of allogeneic adoptive cellular therapies.

01 Dec 2024·Journal of Biochemical and Molecular Toxicology

Double‐Negative T Cells Promote Liver Fibrosis Progression by Regulating Treg/Th17

Article

Author: Qian, Xiaoying ; Li, Wenyan ; Yang, Yi ; Han, Chenyang ; Zhou, Xiaohong ; Zhang, Caiqun ; Wang, Jin ; Pei, Hongyan ; Wu, Shasha

AbstractWe investigated the mechanism whereby double‐negative T cells (DNTs) regulate Treg/Th17 balance to promote the progression of liver fibrosis. Liver fibrosis was induced with carbon tetrachloride (CCl4) in mice. Mouse DNTs were isolated, amplified and injected. The proportions of iTreg (CDF4+CD25+Foxp3+) and Th17 (CD4+IL‐17A+) in peripheral mononuclear cells, spleen and liver were analyzed by flow cytometry, and the cytokine levels were determined through enzyme‐linked immunosorbent assay (ELISA). DNTs could promote the Th17 differentiation and inhibit the iTreg differentiation. The role of DNTs in promoting liver fibrosis progression and tissue inflammation was exerted through activation of IκBa. The use of IL‐17A monoclonal antibody enabled suppression of the DNTs effects, reduction of the Th17 proportion and alleviation of liver fibrosis. Hal could suppress the Th17 differentiation and the effect of DNTs. DNTs can promote the Th17 differentiation through IL‐17A and inhibit iTreg differentiation, thereby facilitating the liver fibrosis progression and microenvironmental inflammation. DNTs are a kind of important immunocytes that promote the liver fibrosis progression.

01 Sep 2024·Plant Biotechnology Journal

UDP‐glycosyltransferase UGT96C10 functions as a novel detoxification factor for conjugating the activated dinitrotoluene sulfonate in switchgrass

Article

Author: Liu, Meifeng ; Su, Kunlong ; Fu, Chunxiang ; Wang, Han ; Wang, Honglun ; Wu, Zhenying ; Wang, Yan ; Liu, Yuchen ; Wang, Yu

SummaryDinitrotoluene sulfonates (DNTSes) are highly toxic hazards regulated by the Resource Conservation and Recovery Act (RCRA) in the United States. The trinitrotoluene (TNT) red water formed during the TNT purification process consists mainly of DNTSes. Certain plants, including switchgrass, reed and alfalfa, can detoxify low concentrations of DNTS in TNT red water‐contaminated soils. However, the precise mechanism by which these plants detoxify DNTS remains unknown. In order to aid in the development of phytoremediation resources with high DNTS removal rates, we identified and characterized 1‐hydroxymethyl‐2,4‐dinitrobenzene sulfonic acid (HMDNBS) and its glycosylated product HMDNBS O‐glucoside as the degradation products of 2,4‐DNT‐3‐SO3Na, the major isoform of DNTS in TNT red water‐contaminated soils, in switchgrass via LC–MS/MS‐ and NMR‐based metabolite analyses. Transcriptomic analysis revealed that 15 UDP‐glycosyltransferase genes were dramatically upregulated in switchgrass plants following 2,4‐DNT‐3‐SO3Na treatment. We expressed, purified and assayed the activity of recombinant UGT proteins in vitro and identified PvUGT96C10 as the enzyme responsible for the glycosylation of HMDNBS in switchgrass. Overexpression of PvUGT96C10 in switchgrass significantly alleviated 2,4‐DNT‐3‐SO3Na‐induced plant growth inhibition. Notably, PvUGT96C10‐overexpressing transgenic switchgrass plants removed 83.1% of 2,4‐DNT‐3‐SO3Na in liquid medium after 28 days, representing a 3.2‐fold higher removal rate than that of control plants. This work clarifies the DNTS detoxification mechanism in plants for the first time, suggesting that PvUGT96C10 is crucial for DNTS degradation. Our results indicate that PvUGT96C10‐overexpressing plants may hold great potential for the phytoremediation of TNT red water‐contaminated soils.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 2	China	RuiChuang Biotechnology Co., Ltd.	29 Jun 2019

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