Submitted May 11, 2006
Accepted July 11, 2006
XIAP targeting sensitizes Hodgkins Lymphoma cells for
cytolytic T cell attack
Hamid Kashkar*, Jens Michael Seeger, Andreas Hombach, Anke Deggerich, Benjamin Yazdanpanah, Olaf Utermohlen, Gerd Heimlich, Hinrich Abken, and Martin Kronke
Medical Microbiology & Immunolology, University of Cologne, Germany
Tumorgenetics, Clinic I Internal Medicine, University of Cologne, Germany
Laboratory of Signal Transduction, NIEHS, NIH, Research Triangle Park, North Carolina, USA
* Corresponding author; email: h.kashkar{at}uni-koeln.de.
The immunosurveillance of Hodgkin's Lymphoma (HL) by
cytotoxic T lymphocytes (CTL) is insufficient and the
clinical experience with adoptive transfer of CTLs is
limited. We have previously reported that defects in
mitochondrial apoptotic pathways and elevated XIAP-
expression confer resistance to different apoptotic
stimuli in HL cells. Here we aimed to develop molecular
strategies to overcome the resistance of HL cells
against CTL-mediated killing via granzyme B (grzB). In
HL cells grzB-induced mitochondrial release of pro-
apoptotic Smac is blocked, which results in complete
abrogation of cytotoxicity mediated by CTLs. Cytosolic
expression of recombinant mature Smac enhanced caspase
activity induced by grzB and restored the apoptotic
response of HL cells. Similarly, down-regulation of XIAP
by RNA interference markedly enhanced the susceptibility
of HL cells for CTL-mediated cytotoxicity. XIAP gene
knock-down sensitized HL cells for killing by antigen-
specific CTLs redirected by grafting with a chimeric
anti-CD30scFv-CD3zeta immunoreceptor. The results
suggest that XIAP targeting by Smac agonists or XIAP-
siRNA can be used as a synergistic strategy for cellular
immunotherapy of Hodgkin's lymphoma.
