Targeted knockdown of Tim3 by short hairpin RNAs improves the function of anti-mesothelin CAR T cells.

Autor: Jafarzadeh L; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Masoumi E; Department of Immunology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran., Mirzaei HR; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Alishah K; Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran., Fallah-Mehrjardi K; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Khakpoor-Koosheh M; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Rostamian H; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Noorbakhsh F; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran., Hadjati J; Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: hajatij@tums.ac.ir.
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2021 Nov; Vol. 139, pp. 1-9. Date of Electronic Publication: 2021 Aug 25.
DOI: 10.1016/j.molimm.2021.06.007
Abstrakt: T-cell immunoglobulin mucin 3 (Tim3) is an immune checkpoint receptor that plays a central role in chimeric antigen receptor (CAR) T cell exhaustion within the tumor microenvironment. This study was aimed to evaluate the effects of targeted-knockdown of Tim3 on the antitumor function of anti-mesothelin (MSLN)-CAR T cells. To knockdown Tim3 expression, three different shRNA sequences specific to different segments of the human Tim3 gene were designed and co-inserted with an anti-MSLN-CAR transgene into lentiviral vectors. To investigate the efficacy of Tim3 targeting in T cells, expression of Tim3 was assessed before and after antigen stimulation. Afterwards, cytotoxic effects, proliferative response and cytokine production of MSLN-CAR T cells and Tim3-targeted MSLN-CAR T cells were analyzed. Our results showed that activation of T cells and MSLN-CAR T cells led to up-regulation of Tim3. Tim3 knockdown significantly decreased its expression in different groups of MSLN-CAR T cells. Tim3 knockdown significantly improved cytotoxic function, cytokine production and proliferation capacity of MSLN-CAR T cells. Our findings indicate that targeted knockdown of Tim3 allows tumor-infiltrating CAR T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby altering the tumor microenvironment from immunosuppressive to immunosupportive via mitigated Tim3 signaling.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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