Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell antitumor capacities for adoptive cell therapy
نویسندگان
چکیده
Background Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or blood T cells genetically redirected by an antitumor TCR CAR induces a strong response in proportion patients with cancer; however, the therapeutic efficacy is often limited rapid decline cell functions. Coadministering supportive cytokines frequently provokes systemic side effects preventing their broad clinical application. We recently showed that can be anchored to membrane functional fashion and cytokine receptor signaling synergize TLR4 CD40 signaling. Here, we aimed at augmenting activation simultaneous through receptor, toll-like TNF-type using IL-18, as prototypes. Methods Genes were expressed on electroporation vitro-transcribed mRNA CD4 + CD8 from healthy donors against melanoma anti-melanotransferrin TILs derived patients. Functional assays included pathways, expression differentiation markers, secretion killing target cells. Results To provide IL-18 costimulation in-cis while avoiding effects, membrane, either alone (memIL-18) fused constitutively active (ca)TLR4 caCD40 domains arranged tandem, creating synthetic ‘all-in-one’ memIL-18-TLR4-CD40 receptor. MemIL-18-TLR4-CD40, but not memIL-18, triggered NF-κB lacking attesting functionality TLR-CD40 moiety. While membrane-anchored was found act mainly in-cis, some in-trans also observed. The electroporated exhibited spontaneous T-bet upregulation IFN-γ TNF-α secretion. Melanoma-induced CAR-T manifested cytolytic activity substantially augmented both constructs, exerting stronger than memIL-18 alone. Conclusions Linking caTLR4 one hybrid transmembrane protein provides three costimulatory pathways engineered molecule, strongly amplifying functions for adoptive therapy cancer.
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ژورنال
عنوان ژورنال: Journal for ImmunoTherapy of Cancer
سال: 2022
ISSN: ['2051-1426']
DOI: https://doi.org/10.1136/jitc-2020-001544