Abstracts (complete list) - Wissenschaft Online

Mareike Schmudde, André Braun, Ulrike Klier, Daniela Pende, Jürgen Sonnemann,
Lorenzo Moretta, James F. Beck, Barbara M. Bröker
Histone deacetylase inhibitors sensitize tumour cells for
cytotoxic effects of natural killer cells
Introduction: Histone deacetylase inhibitors (HDIs) are currently emerging as potent
anti-tumour agents. By influencing the transcription of up to 22 % of genes, they induce
cell cycle arrest, differentiation and/or apoptosis in tumour cells. Beside their direct antitumour
activity, HDIs enhance the cytotoxic effects of ionizing radiation, chemotherapy
and recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). This
raises the question, whether cytotoxic effector functions of natural killer (NK) or T cells
are partially responsible for the anti-tumour effects of HDIs.
Materials and Methods: HDI (SAHA, NaB)-treated tumour cell lines (prostate cancer
PC3, medulloblastoma DAOY) were exposed to IL2-activated human PBMCs. Cell death
was quantified by flow cytometric counting of surviving tumour cells and by 51 Cr-release
assays. The involvement of activating NK receptors in tumour cell recognition was
determined using masking antibodies in the 51Cr-release assays. Surface expression of
NK receptor ligands on tumour cells was measured by flow cytometry.
Results: Both HDIs and PBMCs induced tumour cell death in a dose-dependent manner.
In combination, their effects were synergistic. Killing of tumour cells depended on the
activating NK receptors NKG2D, DNAM-1 and the natural cytotoxicity receptors (NCRs).
HDI-treatment did not result in the engagement of alternative activating NK receptors.
However, it increased the redundancy of the involved receptors. Furthermore, HDIs
increased the expression of the NKG2D ligands MICA and ULBP2.
Conclusions: PBMCs and HDIs synergize in the induction of tumour cell death in vitro.
This indicates that cytotoxic effector functions of the immune system may contribute to
the therapeutic activity of HDIs in tumour patients. On a molecular level, this might be
performed by NK cells, which are more efficiently activated due to increased expression
of activating NK receptor ligands.