Elevated TIM3 expression on bone marrow T cells drives immune dysfunction in early relapsed blood cancer after allogeneic hematopoietic stem cell transplantation.

IF 13.5 1区 医学 Q1 HEMATOLOGY
Thi Thuy Duong Pham, Su-Young Choi, Jeong Suk Koh, Bu-Yeon Heo, Sang-Woo Lee, Myung-Won Lee, Wonhyoung Seo, Yunseon Jang, Jung-Hyun Park, Deog-Yeon Jo, Seungyeul Yoo, Jaeyul Kwon, Ik-Chan Song
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Abstract

Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading cause of treatment failure in patients with hematologic malignancies. To better understand the mechanisms underlying early relapse (ER), we comprehensively explored the expression of inhibitory receptors (IRs) in bone marrow (BM) T cells at differentiation stage and examined transcriptional differences. Among the evaluated IRs, TIM3 was significantly upregulated in CD3+T cells of patients with ER compared to patients with complete remission (CR). Notably, double-negative T (DNT) cells, a unique subset with MHC-independent cytotoxic potential, constituted a high proportion of BM T cells and expressed increased TIM3 expression in ER patients. Moreover, regulatory T cells (Tregs) showed elevated TIM3 levels, contributing to an immunosuppressive microenvironment after allo-HSCT. Transcriptomic analysis revealed downregulation of cytotoxic granules and effector genes in DNT cells from ER patients. Functional assays demonstrated that TIM3 blockade with sabatolimab restored T cell cytotoxicity, leading to enhanced leukemia cell apoptosis in ER patients. These findings highlight TIM3 as a critical regulator of T cell exhaustion and immune suppression in patients with ER and provide a rationale for the therapeutic use of TIM3 blockade in preventing and treating relapses after allo-HSCT.

骨髓T细胞TIM3表达升高驱动异基因造血干细胞移植后早期复发血癌的免疫功能障碍。
同种异体造血干细胞移植(同种异体造血干细胞移植)后复发仍然是恶性血液病治疗失败的主要原因。为了更好地了解早期复发(ER)的机制,我们全面探索了骨髓(BM) T细胞分化阶段抑制受体(IRs)的表达,并检测了转录差异。在评估的ir中,与完全缓解(CR)患者相比,ER患者的CD3+T细胞中的TIM3显著上调。值得注意的是,双阴性T细胞(DNT)是一种独特的亚群,具有与mhc无关的细胞毒性潜力,在BM T细胞中占很大比例,并且在ER患者中表达增加的TIM3表达。此外,调节性T细胞(Tregs)显示TIM3水平升高,有助于同种异体造血干细胞移植后的免疫抑制微环境。转录组学分析显示,ER患者DNT细胞中细胞毒性颗粒和效应基因下调。功能分析表明,用sabatolimab阻断TIM3可恢复T细胞毒性,导致ER患者白血病细胞凋亡增强。这些发现强调TIM3是ER患者T细胞衰竭和免疫抑制的关键调节因子,并为使用TIM3阻断剂预防和治疗同种异体造血干细胞移植后复发提供了理论依据。
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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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