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    Pembrolizumab interferes with the differentiation of human FOXP3(+)-induced T regulatory cells, but not with FOXP3 stability, through activation of mTOR

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    Authors
    Sasidharan, Nair V
    Toor, SM
    Taouk, G
    Pfister, G
    Ouararhni, K
    Alajez, NM
    Elkord, Eyad
    Affiliation
    Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    Programmed cell death 1 (PD-1) is critical for T regulatory cells (Tregs) to maintain peripheral tolerance to self-antigens. In the tumor microenvironment, interaction between PD-1 and its ligands supports tumor immune evasion. Pembrolizumab blocks interactions of PD-1 with its ligands, enhancing antitumor and clinical responses. We and others have reported that pembrolizumab does not affect function or phenotype of thymic-derived Tregs; however, little is known about its effect on extrathymic differentiation of peripheral Tregs. In this study, we investigated the effect of pembrolizumab on in vitro-induced Tregs (iTregs). Our work showed that PD-1 blockade interferes with iTreg differentiation and has no potential effect on the stability of FOXP3 after differentiation. Additionally, we found that both nontreated and pembrolizumab-treated iTregs were suppressive. However, pembrolizumab-treated iTregs were relatively less suppressive in higher Treg ratios and failed to produce IL-10 compared with their nontreated counterparts. Different methods including transcriptomic analyses confirmed that the downregulation of FOXP3 was mediated by activating mTOR and STAT1 and inhibiting MAPK pathways, shifting the iTreg polarization in favor of Th1 and Th17 subsets. To confirm the role of mTOR activation, we found that rapamycin diminished the effect of pembrolizumab-mediated downregulation of FOXP3. Ingenuity pathway analysis revealed that pembrolizumab-treated iTregs showed upregulation of genes promoting DNA repair and immune cell trafficking, in addition to downregulation of genes supporting cellular assembly and organization. To our knowledge, this is the first study to show that pembrolizumab interferes with differentiation of human FOXP3+ iTregs and to disclose some of the molecular pathways involved.
    Citation
    Sasidharan Nair V, Toor SM, Taouk G, Pfister G, Ouararhni K, Alajez NM, et al. Pembrolizumab Interferes with the Differentiation of Human FOXP3(+)-Induced T Regulatory Cells, but Not with FOXP3 Stability, through Activation of mTOR. J Immunol. 2020;204(1):199-211.
    Journal
    Journal of immunology
    URI
    http://hdl.handle.net/10541/622680
    DOI
    10.4049/jimmunol.1900575
    PubMed ID
    31801817
    Additional Links
    https://dx.doi.org/10.4049/jimmunol.1900575
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.4049/jimmunol.1900575
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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