Repository of Research and Investigative Information

Repository of Research and Investigative Information

Ilam University of Medical Sciences

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

Mon Oct 3 04:54:28 2022

(2021) Targeted knockdown of Tim3 by short hairpin RNAs improves the function of anti-mesothelin CAR T cells. Molecular immunology. pp. 1-9. ISSN 1872-9142 (Electronic) 0161-5890 (Linking)

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Official URL: https://www.ncbi.nlm.nih.gov/pubmed/34450537

Abstract

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.

Item Type: Article
Creators:
CreatorsEmail
Jafarzadeh, L.UNSPECIFIED
Masoumi, E.UNSPECIFIED
Mirzaei, H. R.UNSPECIFIED
Alishah, K.UNSPECIFIED
Fallah-Mehrjardi, K.UNSPECIFIED
Khakpoor-Koosheh, M.UNSPECIFIED
Rostamian, H.UNSPECIFIED
Noorbakhsh, F.UNSPECIFIED
Hadjati, J.UNSPECIFIED
Keywords: Chimeric antigen receptor Mesothelin Targeted knockdown Tim3 Tumor microenvironment
Divisions:
Page Range: pp. 1-9
Journal or Publication Title: Molecular immunology
Journal Index: Pubmed
Volume: 139
Identification Number: https://doi.org/10.1016/j.molimm.2021.06.007
ISSN: 1872-9142 (Electronic) 0161-5890 (Linking)
Depositing User: مهندس مهدی شریفی
URI: http://eprints.medilam.ac.ir/id/eprint/3623

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