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