Clinically relevant SMAC mimetics do not enhance human T cell proliferation or cytokine production

Secondary mitochondria-derived activator of caspases (SMAC) mimetics are being tested in dozens of clinical trials to treat cancer. These targeted therapies mimic endogenous molecules that promote apoptosis by antagonizing inhibitors of apoptosis (IAPs), which are commonly overexpressed in cancer cells. In T cells, IAPs function to restrain non-canonical NF-kB signaling. Thus, it has been suggested that in addition to their direct anti-cancer mechanism of action, SMAC mimetics may activate T cells, thereby promoting anti-tumor immunity. Here, we tested the effect of three clinically relevant SMAC mimetics on the proliferation and activation of primary human T cells. As previously reported, SMAC mimetics killed tumor cells and activated non-canonical NF-kB in T cells at clinically relevant doses. Surprisingly, none of the SMAC mimetics augmented T cell proliferation or effector function. These results question the assumption that SMAC mimetics are likely to boost anti-tumor immunity in cancer patients.