| Popis: |
Second mitochondria-derived activator of caspase (SMAC) mimetics are small molecule drugs currently in cancer clinical trials. They are thought to act by antagonizing inhibitors of apoptosis (IAPs), which are often overexpressed in malignancies. However, in leukocytes, IAPs inhibit cell activation via antagonizing non-canonical NF-κB. This suggests that, paradoxically, while SMAC mimetics can induce apoptosis in cancer cells, they may enhance activation in T cells. The aim of this project is to determine whether human T cell proliferation and effector function are affected by SMAC mimetics. We previously showed that non-canonical NF-κB plays an essential intrinsic role in T cell activation in mice. Here, we show that the SMAC mimetic TL32711 (Birinapant) activates non-canonical NF-κB in primary human T cells. Doses of SMAC mimetics that induce 100% apoptosis in the breast cancer cell line, MDA-MB-231, do not affect T cell viability. Birinapant dose-dependently increases IL-2 secretion, but the effects of SMAC mimetics on T cell proliferation and Th1 cytokine production are complex and depend on availability of costimulation and accessory cells. Endogenous T cells can combat cancer if properly stimulated, a fact underlined by the efficacy of checkpoint blockade. Thus, understanding the effect of SMAC mimetics on T cell responses is a critical consideration in using SMAC mimetics to treat cancer and for designing combination therapies. |
