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

lHuman cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis

Dotti, G; Savoldo, B; Pule, M; Straathof, KC; Biagi, E; Yvon, E; Vigouroux, S; ... Rooney, CM; + view all (2005) lHuman cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis. BLOOD , 105 (12) 4677 - 4684. 10.1182/blood-2004-08-3337. Green open access

[thumbnail of 7068.pdf]
Preview
PDF
7068.pdf

Download (251kB)

Abstract

Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Fas(low) and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (c) 2005 by The American Society of Hematology.

Type: Article
Title: lHuman cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood-2004-08-3337
Keywords: HUMAN PERIPHERAL-BLOOD, LIGAND EXPRESSION, TUMOR ESCAPE, IN-VIVO, CELLS, MELANOMA, TRANSMEMBRANE, PROTEASES, SELECTION, LYMPHOMA
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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/7068
Downloads since deposit
199Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item