SMAC/DIABLO (second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI) is a proapoptotic mitochondrial protein that is released in response to various apoptotic stimuli. Molecular mimetics of SMAC are being investigated for use in cancer treatment, but their activities in vivo have not been fully characterized.
In a recent study, Emeagi and colleagues from Vrije Universiteit Brussel, Belgium, showed that SMAC mimetics induce cancer cell death via a proinflammatory effect that is accompanied by an adaptive antitumor immune response. Transduction with lentiviral vectors encoding a cytosolic form of a SMAC mimetic (LV-tSMAC) resulted in apoptosis of cancer cells of different histologic origins, and treatment of tumor-bearing mice with the SMAC mimetic resulted in induction of apoptosis, activation of antitumor immunity, and prolonged survival.
The antitumor immune response included increased levels of tumor-infiltrating lymphocytes with low expression of PD-1 (an inhibitory molecule on activated T cells that plays a role in regulating immune response), high lytic capacity, and high levels of the proinflammatory cytokine interferon-γ. Levels of regulatory T cells were reduced in vivo, activation of tumor-specific cytotoxic T cells was observed in vivo, and activation of tumor-specific T cells by dendritic cells isolated from tumor-draining lymph nodes was observed in vitro.
As stated by the investigators, “Our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer.” ■
Emeagi PU, et al: Cancer Res 72:1342-1352, 2012.