Neuroblastoma as a target for effector mechanisms of the immune system
Author: De Geer, Anna
Date: 2007-06-14
Location: Radiumhemmets föreläsningssal, Karolinska Universitetssjukhuset, Solna
Time: 09.30
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
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thesis.pdf (1.186Mb)
Abstract
Neuroblastoma (NB) is the most common solid extracranial tumor in
children. Despite intensive multimodal treatment, the prognosis for
high-risk NB patients remains poor and therefore new treatment modalities
are needed. The main aim of my studies was to assess NB as a target for
cytotoxic T lymphocyte (CTL)-mediated immunotherapy. CTLs induce target
cell death through two major pathways, namely the cytotoxic granule
exocytosis- and the death receptor-mediated pathway. While an efficient T
cell-mediated lysis through the release of perforin/granzyme-containing
cytotoxic granules requires the expression of the relevant HLA class I
complexes as well as adhesion molecules on the target cells, killing
through the death receptor pathway involves the binding of the ligands to
death receptors in the tumor cell membrane, and requires an intact
intracellular molecular machinery that conveys the signal to execute
tumor cell death. However, a number of features including low or absent
surface HLA class I as well as a defective expression of caspase-8, may
hamper the development of immunotherapeutic modalities for NB.
Nevertheless, strategies to enhance the immunogenicity of NB cells could
render them into good targets for CTL-mediated immunotherapy.
Alternatively, NB cells can be targeted by means of bystander activated
CTLs in an HLA-independent fashion. Both these approaches have been
investigated in the studies presented in this thesis.
We demonstrated that retinoids, differentiating agents currently in use
as a treatment modality for high-risk NB, act as enhancers of HLA class I
antigen processing and presentation as well as increase the
susceptibility of NB to CTL-mediated effector mechanisms. We found that
retinoids induced the expression of proteolytic and regulatory subunits
of the immunoproteasome, increased the half-life of HLA class I
complexes, and enhanced the sensitivity of NB cells to both HLA class
I-restricted peptide-specific and HLA class I non-restricted lysis by
CTLs. Our data suggest that the application of retinoids and CTL-based
immunotherapy may be an effective combination for the treatment of NB
(Paper I). Though numerous studies have demonstrated the ability of IFNγ
to induce components of the antigen processing machinery (APM) in NB, the
impact on subsequent tumor recognition by CTLs has not been investigated
in detail. Therefore, we investigated the IFNγ-induced effects on
selected components of the APM in NB cells as well as on CTL recognition.
Although IFNγ-treatment efficiently induced surface HLA class I on NB
cells, this effect did not translate into an efficient increase in
HLA-restricted killing by CTLs. We suggest two possible molecular
explanations for this phenomenon; (i) an IFNγ-induced expression of the
inhibitory HLA-E on NB cells, and/or (ii) a decreased susceptibility of
IFNγ-treated tumor cells to the cytolytic granule content of CTLs (Paper
III).
To investigate whether CTLs may eliminate NB cells in an HLA-independent
manner without the involvement of perforin/granzyme-mediated
cytotoxicity, we used NB-non-specific CTLs activated on third party
targets as well as soluble factors released from these CTLs. We found
that both caspasedependent and-independent cell death were induced in NB
cells in a bystander manner, and, in addition, TNFα released from
activated CTLs was defined as an important effector molecule (Paper II).
Besides inducing NB cell death, soluble factors released by activated
CTLs modulated the levels of cell surface molecules implicated in
HLA-restricted and HLA-independent NB cell recognition, induced the
expression of caspase-8, as well as increased the susceptibility of NB
cells to death receptor-mediated killing. Importantly, soluble factors
released by activated CTLs skewed the surface immune phenotype of both
long term cultured and primary NB cells (Paper IV).
Altogether, the results presented in this thesis suggest that recruiting
activated CTLs into the proximity of the tumor may have a therapeutic
effect in patients with NB. CTLs may simultaneously activate different
death pathways and override the “silent” immune phenotype of NB cells. We
also suggest that CTL-mediated therapy could be combined with retinoid
treatment of NB.
List of papers:
I. Vertuani S, De Geer A, Levitsky V, Kogner P, Kiessling R, Levitskaya J (2003). "Retinoids act as multistep modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes." Cancer Res 63(22): 8006-13
Pubmed
II. De Geer A, Kiessling R, Levitsky V, Levitskaya J (2006). "Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion." J Immunol 177(11): 7540-50
Pubmed
III. De Geer A, Rakhmanaliev E, Handke D, Carlson LM, Kiessling R, Kogner P, Seliger B, Levitskaya J (2007). "Interferon gamma-induced changes either do not promote or negatively affect MHC class I-restricted T-cell recognition of neuroblastoma cells." (Submitted)
IV. De Geer A, Carlson LM, Kogner P, Levitskaya J (2007). "Soluble factors released by activated cytotoxic T lymphocytes interfere with death receptor pathways in neuroblastoma." (Submitted)
I. Vertuani S, De Geer A, Levitsky V, Kogner P, Kiessling R, Levitskaya J (2003). "Retinoids act as multistep modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes." Cancer Res 63(22): 8006-13
Pubmed
II. De Geer A, Kiessling R, Levitsky V, Levitskaya J (2006). "Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion." J Immunol 177(11): 7540-50
Pubmed
III. De Geer A, Rakhmanaliev E, Handke D, Carlson LM, Kiessling R, Kogner P, Seliger B, Levitskaya J (2007). "Interferon gamma-induced changes either do not promote or negatively affect MHC class I-restricted T-cell recognition of neuroblastoma cells." (Submitted)
IV. De Geer A, Carlson LM, Kogner P, Levitskaya J (2007). "Soluble factors released by activated cytotoxic T lymphocytes interfere with death receptor pathways in neuroblastoma." (Submitted)
Issue date: 2007-05-24
Rights:
Publication year: 2007
ISBN: 978-91-7357-216-3
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