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10.1111/cei.12688

http://scihub22266oqcxt.onion/10.1111/cei.12688
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C4608512!4608512!26212048
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suck abstract from ncbi


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pmid26212048      Clin+Exp+Immunol 2015 ; 182 (2): 220-9
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  • Messenger RNA encoding constitutively active Toll-like receptor 4 enhances effector functions of human T cells #MMPMID26212048
  • Pato A; Eisenberg G; Machlenkin A; Margalit A; Cafri G; Frankenburg S; Merims S; Peretz T; Lotem M; Gross G
  • Clin Exp Immunol 2015[Nov]; 182 (2): 220-9 PMID26212048show ga
  • Adoptive T cell therapy of cancer employs a large number of ex-vivo-propagated T cells which recognize their targets either by virtue of their endogenous T cell receptor (TCR) or via genetic reprogramming. However, both cell-extrinsic and intrinsic mechanisms often diminish the in-vivo potency of these therapeutic T cells, limiting their clinical efficacy and broader use. Direct activation of human T cells by Toll-like receptor (TLR) ligands induces T cell survival and proliferation, boosts the production of proinflammatory cytokines and augments resistance to regulatory T cell (Treg) suppression. Removal of the TLR ligand-binding region results in constitutive signalling triggered by the remaining cytosolic Toll/interleukin-1 receptor (TIR) domain. The use of such TIR domains therefore offers an ideal means for equipping anti-tumour T cells with the arsenal of functional attributes required for improving current clinical protocols. Here we show that constitutively active (ca)TLR-4 can be expressed efficiently in human T cells using mRNA electroporation. The mere expression of caTLR-4 mRNA in polyclonal CD8 and CD4 T cells induced the production of interferon (IFN)-?, triggered the surface expression of CD25, CD69 and 4-1BB and up-regulated a panel of cytokines and chemokines. In tumour-infiltrating lymphocytes prepared from melanoma patients, caTLR-4 induced robust IFN-? secretion in all samples tested. Furthermore, caTLR-4 enhanced the anti-melanoma cytolytic activity of tumour-infiltrating lymphocytes and augmented the secretion of IFN-?, tumour necrosis factor (TNF)-? and granulocyte?macrophage colony-stimulating factor (GM-CSF) for at least 4 days post-transfection. Our results demonstrate that caTLR-4 is capable of exerting multiple T cell-enhancing effects and can potentially be used as a genetic adjuvant in adoptive cell therapy.
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