of the Max - MDC

Molecular Mechanisms of
Immune Evasion in Tumor
Biology and Herpesvirus
Infection
Armin Rehm
(Helmholtz Fellow)
Our work is focused on the role of immunosurveillance in
tumor biology. Tumor cells employ a multitude of pathways
to evade the host’s immune response, and some of those
mechanisms can be linked conceptually with the strategies
employed by persistent Herpesviruses for their own benefit.
The molecular and systemic study of immunoevasive strategies
emerges as a prerequisiste for the improvement of current
immunological treatment options for the cure of cancer.
Pathogenetic implications of disturbed
intracellular vesicle transport routes for tumor
development
In cancer biology, the identification of novel diagnostic
markers, but also the identification of target structures in
tumor-specific immunotherapies hinges on the existence of
tumor-associated antigens. We have characterized an estrogen-inducible
tumor-associated antigen, EBAG9, which
upon overexpression causes the deposition of truncated O-
linked glycans (Tn and TF) on non-secretory cell lines. Those
aberrant glycan structures are putatively linked with tumor
cell adhesion and metastasis, thus we focused on the cell
biological mechanisms of their generation. We have applied
a multidisciplinary approach to elucidate the functional link
between EBAG9 overexpression and the occurrence of these
tumor-associated glycan structures. The identification of
the COPI complex as interaction partner pointed to the
involvement of EBAG9 in the regulation of the early secretory
transport pathway. Functionally, EBAG9 causes the dislocation
of glycan-modifying enzymes and a disturbance of
the ER to cis-Golgi vesicle trafficking route, thus leading to
a maturation and forward transport blockade of glycoproteins
(see Figure below) in epithelial cell lines. Our results
define a novel pathogenetic pathway employed by carcinoma
cells, the direct consequences of which are currently
explored in systemic tumor models.
Modulation of the secretory pathway plays a pivotal role in
cytotoxic T cell-mediated tumor immunosurveillance
(in cooperation with U.E. Höpken, W. Uckert,
B. Erdmann, MDC)
While we have elucidated the functional implications of
estrogen-tunable EBAG9 overexpression in carcinoma cells,
the question emerges as to whether estrogen has a concurrent
impact on T cell-mediated tumor immunosurveillance.
Cytotoxic T lymphocytes (CTL) are essential for immunosurveillance
and score cells for the display of tumor-derived
peptides. In neuronal cells, we have identified the SNAREassociated
molecule Snapin as an interaction partner which
pointed to a role of EBAG9 as a switch between the constitutive
and regulated secretory pathway. For target cell
destruction, CTLs employ polarized secretion of lytic granules,
a Calcium regulated process that parallels many
aspects of synaptic vesicle release at the neuronal synapse.
To study the function of EBAG9 in vivo, we generated knockout
mice and characterized the consequences of its deletion
in CTL-mediated immune responses. Loss of EBAG9 amplifies
the release of lytic granules and confers CTLs with an
enhanced cytolytic activity, in all likelihood through
improved formation of fusion- and release-competent
secretory lysososomes. With regard to tumor immunosurveillance
and tumor immunotherapy, modulating the cell
biological roadblocks in T cell activation and cytolytic
capacity on a single cell level emerges as a strategy to
increase avidity and to strengthen anti tumor T cell
efficiency.
Identification and therapeutic inhibition of
pathogenetic pathways in lymphoma-stroma
interactions
(in cooperation with U.E. Höpken, M. Lipp, I.
Anagnostopoulos, H. Stein, MDC, Charité, Berlin)
The crosstalk between lymphoid tumor cells and their
microenvironment provides pivotal signals for the initiation
and progression of hematopoietic malignancies. In contrast
to leukemia cells that develop an increasingly autonomous
and microenvironmentally uncontrolled proliferation capacity,
some B cell non-Hodgkin lymphomas (NHL) provide
striking examples for a functional interaction between lymphoma
cells and non-malignant stroma cells. Thus, it has
become increasingly important to define the molecular
pathways that allow the communication between accessory
cells and malignant B cells.
As a paradigm for tumor cell and stroma interactions, we
have focused on the primary mediastinal B cell lymphoma
(PMBL). By taking advantage of the chemokine system, we
assessed functionally and phenotypically the relationship
between PMBL and their supposed ancestors, thymic B cells,
and secondly, we compared the chemokine/chemokine
126 Cancer Research