UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Novel Fas-TNFR chimeras that prevent Fas ligand-mediated kill and signal synergistically to enhance CAR T cell efficacy

McKenzie, Callum; El-Kholy, Mohamed; Parekh, Farhaan; Robson, Mathew; Lamb, Katarina; Allen, Christopher; Sillibourne, James; ... Pule, Martin; + view all (2023) Novel Fas-TNFR chimeras that prevent Fas ligand-mediated kill and signal synergistically to enhance CAR T cell efficacy. Molecular Therapy - Nucleic Acids , 32 pp. 603-621. 10.1016/j.omtn.2023.04.017. Green open access

[thumbnail of 1-s2.0-S2162253123001038-main.pdf]
Preview
PDF
1-s2.0-S2162253123001038-main.pdf - Published Version

Download (4MB) | Preview

Abstract

The hostile tumor microenvironment limits the efficacy of adoptive cell therapies. Activation of the Fas death receptor initiates apoptosis and disrupting these receptors could be key to increasing CAR T cell efficacy. We screened a library of Fas-TNFR proteins identifying several novel chimeras that not only prevented Fas ligand-mediated kill, but also enhanced CAR T cell efficacy by signaling synergistically with the CAR. Upon binding Fas ligand, Fas-CD40 activated the NF-κB pathway, inducing greatest proliferation and IFN-γ release out of all Fas-TNFRs tested. Fas-CD40 induced profound transcriptional modifications, particularly genes relating to the cell cycle, metabolism, and chemokine signaling. Co-expression of Fas-CD40 with either 4-1BB- or CD28-containing CARs increased in vitro efficacy by augmenting CAR T cell proliferation and cancer target cytotoxicity, and enhanced tumor killing and overall mouse survival in vivo. Functional activity of the Fas-TNFRs were dependent on the co-stimulatory domain within the CAR, highlighting crosstalk between signaling pathways. Furthermore, we show that a major source for Fas-TNFR activation derives from CAR T cells themselves via activation-induced Fas ligand upregulation, highlighting a universal role of Fas-TNFRs in augmenting CAR T cell responses. We have identified Fas-CD40 as the optimal chimera for overcoming Fas ligand-mediated kill and enhancing CAR T cell efficacy.

Type: Article
Title: Novel Fas-TNFR chimeras that prevent Fas ligand-mediated kill and signal synergistically to enhance CAR T cell efficacy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omtn.2023.04.017
Publisher version: http://doi.org/10.1016/j.omtn.2023.04.017
Language: English
Additional information: © 2023 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: MT: Oligonucleotides: Therapies and Applications, apoptosis, Fas ligand, adoptive cell therapy, CAR Tcells, synthetic biology, immunotherapy, T cell signaling, cancer therapy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10169885
Downloads since deposit
17Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item