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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4677-4684.
Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-08-3337.
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Submitted August 27, 2004
Accepted February 5, 2005
Human cytotoxic T-lymphocytes with reduced sensitivity to Fas-induced apoptosis
Gianpietro Dotti*, Barbara Savoldo, Martin Pule, Karin C Straathof, Ettore Biagi, Eric Yvon, Stephane Vigouroux, Malcolm K Brenner, and Cliona M Rooney
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
* Corresponding author; email: gdotti{at}bcm.tmc.edu.
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 anti-tumor host immune response. Since Epstein Barr Virus (EBV)-associated tumors such as Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T-lymphocytes (EBVCTLs) could be modified to resist this evasion strategy. We show that long-term downmodulation 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 to control cells, and showed minimal cleavage of the caspase3 substrate ADP-ribose polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Faslow and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBVCTLs. In particular, it did not lead to their autonomous growth since the modified EBVCTLs remained polyclonal, and their survival and proliferation retained dependence on antigen specific stimulation and on the presence of other physiological 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.
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