SMAC mimetics inhibit human T cell proliferation and fail to augment type 1 cytokine responses.

• SMAC mimetics, which antagonize IAPs, activate non-canonical NF-κB in human T cells. • Birinapant, LCL161, and BV6 were tested for stimulatory effects on T cells. • Contrary to prediction, SMAC mimetics decreased CD4 and CD8 T cell proliferation. • SMAC mimetic-mediated inhibition was strongest with limiting TCR signal. • Birinapant decreased the proportion of TNFα/IFNγ double-producing T cells. Second mitochondria-derived activator of caspases (SMAC) mimetics are small molecule drugs that mimic the activity of the endogenous SMAC protein. SMAC and SMAC mimetics antagonize inhibitors of apoptosis proteins (IAPs), thereby sensitizing cells to apoptosis. As such, SMAC mimetics are being tested in numerous clinical trials for cancer. In addition to their direct anti-cancer effect, it has been suggested that SMAC mimetics may activate T cells, thereby promoting anti-tumor immunity. Here, we tested the effect of three clinically relevant SMAC mimetics on activation of primary human T cells. As previously reported, SMAC mimetics killed tumor cells and activated non-canonical NF-κB in T cells at clinically relevant doses. Surprisingly, none of the SMAC mimetics augmented T cell responses. Rather, SMAC mimetics impaired T cell proliferation and decreased the proportion of IFNγ/TNFα double-producing T cells. These results question the assumption that SMAC mimetics are likely to boost anti-tumor immunity in cancer patients. [ABSTRACT FROM AUTHOR]