Abstract Book 2010 - CIMT Annual Meeting

087 Lutz-Nicoladoni | Tumor biology & interaction with the immune system
Reinforcement of Cancer Immunotherapy by Adoptive
Transfer of cblb-deficient Cytotoxic T Lymphocytes
combined with a Dentritic Cell Vaccine
Christina Lutz-Nicoladoni 1,2 , Patrizia Stoitzner 3 , Magdalena Pircher 1,2 , Stephanie Wallner
1,2 , Thomas Gruber 4 , Anna Maria Wolf 1,2 , Günther Gastl 1,2 , Josef Penninger 5 , Gottfried
Baier 4 , Dominik Wolf 1,2
1 Tyrolean Cancer Research Institute, Tumorimmunology, Innsbruck, Austria
2 Medical University Innsbruck, Internal Medicine V, Hematology and Oncology, Innsbruck, Austria
3 Medical University Innsbruck, Department of Dermatology and Venerology, Austria
4 Medical University Innsbruck, Department for Medical Genetics, Molecular and Clinical Pharmacology, Austria
5 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
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During the last decades rapid progress in immuno-
logy facilitated the development of tumor therapy
based on cell transfer. Autologous tumorinfiltrating
lymphocytes (TILs) are transferred after ex
vivo clonal expansion or ex vivo transduction with
tumor antigen specific T cell receptors (TCR) and
subsequent expansion into patients. Adoptive T
cell transfers (ATC) are often combined with lymphodepleting
therapies. However, the success of
cancer immunotherapy is limited by potent endogenous
immune-evasion mechanisms, which are
centrally mediated by transforming growth factor
beta TGF-β. The RING E3 ubiquitin ligase casitas B
cell lymphoma (Cbl-b) is a negative key regulator
of T cell activation. Cblb-deficient T lymphocytes
are uncoupled from the requirement of CD28 costimulation,
are anergy-resistent and resistant to inhibition
by TGF-β. As a consequence, cblb-deficient
animals reject tumors via cytotoxic CD8+ T cells
(CTLs), which makes Cbl-b an ideal target in adoptive
T cell transfer therapy.
Here we provide evidence that cblb-/- CTLs are
hyper-responsive to TCR/CD28-stimulation in vitro
and protected from the negative effects induced by
TGF-β. Nevertheless and unexpectedly, adoptive
transfer of polyclonal, non TCR-transgenic cblb-deficient
CTLs into tumor bearing immunocompetent
wildtype (wt) mice is not sufficient to reject B16ova
or EG7 tumors in vivo. Thus, cblb-deficient transferred
CD8+ T cells were in vivo re-activated by a
dendritic cell (DC) vaccine (i.e. SIINFEKL-pulsed
DC). In strict contrast to ATC monotherapy, this approach
now delayed tumor outgrowth and significantly
increased survival rates, which is paralleled
by an increased CTL infiltration rate to the tumor
site as well as enrichment of tumor antigen-specific
and interferon-gamma (IFN-g)-secreting CTLs in
the draining lymphnodes. Moreover, in vivo cytolytic
activity was increased in tumor bearing mice
treated with DCs and cblb-deficient CTLs compared
to those treated with DCs plus wt CTLs.
In summary, we provide experimental evidence that
genetic inactivation of Cbl-b in polyclonal, non-TCR
transgenic adoptively transferred CTLs serves as a
novel “adjuvant approach”, suitable to augment the
effectiveness of established anti-cancer immunotherapy
in immuno-competent recipients.