Second mitochondria-derived activator of caspase (SMAC) mimetic potentiates tumor susceptibility toward natural killer cell-mediated killing

Abstract

Resistance to apoptosis is a hallmark of cancer, and represents an important mechanism of how tumor cells resist immune cell destruction. Mitochondria are the central regulators of the apoptotic machinery by releasing pro-apoptotic factors including cytochrome c and second mitochondria-derived activator of caspase (SMAC) upon mitochondrial outer membrane permeabilization (MOMP). Small molecules activating MOMP such as BH3 mimetics or antagonizers of the inhibitor of apoptosis proteins (IAPs) such as SMAC mimetics have recently engendered new optimism for a more individualized and effective cancer therapy. Here we show that a SMAC mimetic potentiates cancer cell killing by natural killer (NK) cells through reactivation of tumor cell apoptosis. Specifically, the SMAC mimetic enhances the susceptibility of tumor cells toward NK cell-mediated effector mechanisms involving death receptors and cytolytic granules containing perforin and granzymes by relieving caspase activity. Our data highlight for the first time the specific use of SMAC mimetics for boosting immune cell-mediated immunotherapy, representing a novel and promising approach in the treatment of cancer.

Keywords::

• Adoptive cellular therapies
• SMAC mimetic
• lymphoma and Hodgkin disease
• apoptosis
• NK cells
• cellular immunotherapy
• cancer
• mitochondria
• IAPs
• signal transduction
• cell cycle and BH3 mimetics

Acknowledgements

SMAC mimetic (compound A) and the control compound (compound B) were kindly provided by TetraLogic Pharmaceuticals, Malvern, PA, USA.

We are grateful to Dr. Emma Ariola and Arlene Forte (Abbott Laboratories) and colleagues for the provision of ABT-737.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

We acknowledge support from SFB832 (grants to H. Kashkar), German Cancer Aid (Die Deutsche Krebshilfe) (grants to H. Kashkar and to A. Hombach), the German Research Foundation (DFG) and Deutsche José Carreras-Leukämie Stiftung (grant to H. Abken).

Notice of Correction

The version of this article published online ahead of print on 26th June 2013 contained an error in the title. The title “Second mitochondria-derived activator of caspase mimetic (SMAC) potentiates tumor susceptibility toward natural killer cell-mediated killing” should have read “Second mitochondria-derived activator of caspase (SMAC) mimetic potentiates tumor susceptibility toward natural killer cell-mediated killing”. The error has been corrected for this version.