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

ABSTRACT: 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.

SUBMITTER: Burton AM

PROVIDER: S-EPMC10319349 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Burton Ashley M AM Ligman Brittany R BR Kearney Claire A CA Murray Susan E SE

Cellular immunology 20230118

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 ...[more]

PMID: 36706656

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Project description:Smac/DIABLO is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Smac promotes apoptosis at least in part through antagonizing inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP-1, and cIAP-2. Smac interacts with these IAPs via its N-terminal AVPI binding motif. There has been an enormous interest in academic laboratories and pharmaceutical companies in the design of small-molecule Smac mimetics as potential anticancer agents. This task is particularly challenging because it involves targeting protein-protein interactions. Nevertheless, intense research has now generated potent, specific, cell-permeable small-molecule peptidomimetics and nonpeptidic mimetics. To date, two types of Smac mimetics have been reported, namely, monovalent and bivalent Smac mimetics. The monovalent compounds are designed to mimic the binding of a single AVPI binding motif to IAP proteins, whereas the bivalent compounds contain two AVPI binding motif mimetics tethered together through a linker. Studies from several groups have clearly demonstrated that both monovalent and bivalent Smac mimetics not only enhance the antitumor activity of other anticancer agents but also can induce apoptosis as single agents in a subset of human cancer cell lines in vitro and are capable of achieving tumor regression in animal models of human cancer. In general, bivalent Smac mimetics are 100-1000 times more potent than their corresponding monovalent Smac mimetics in induction of apoptosis in tumor cells. However, properly designed monovalent Smac mimetics can achieve oral bioavailability and may have major advantages over bivalent Smac mimetics as potential drug candidates. In-depth insights on the molecular mechanism of action of Smac mimetics have been provided by several independent studies. It was shown that Smac mimetics induce apoptosis in tumor cells by targeting cIAP-1/-2 for the rapid degradation of these proteins, which leads to activation of nuclear factor kappaB (NF-kappaB) and production and secretion of tumor necrosis factor alpha (TNFalpha). TNFalpha promotes formation of a receptor-interacting serine-threonine kinase 1 (RIPK1)-dependent caspase-8-activating complex, leading to activation of caspase-8 and -3/-7 and ultimately to apoptosis. For the most efficient apoptosis induction, Smac mimetics also need to remove the inhibition of XIAP to caspase-3/-7. Hence, Smac mimetics induce apoptosis in tumor cells by targeting not only cIAP-1/-2 but also XIAP. The employment of potent, cell-permeable, small-molecule Smac mimetics has yielded important insights into the regulation of apoptosis by IAP proteins. To date, at least one Smac mimetic has been advanced into clinical development. Several other Smac mimetics are in an advanced preclinical development stage and are expected to enter human clinical testing for the treatment of cancer in the near future.

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

Publications

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

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