ABSTRACT
The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC-to-TNF-α-mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF-α by engaging the nuclear factor κB (NF-κB) transcriptional pathway. Moreover, the promotion of TNF-α expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF-α production and signaling will help us further understand TNF-α biology and provide insight into mechanisms relevant to cancer and inflammatory disease.
Subject(s)
Biomimetic Materials/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Neoplasms/metabolism , Signal Transduction/drug effects , Sp3 Transcription Factor/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis Regulatory Proteins/metabolism , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/metabolism , Mice , Mitochondrial Proteins/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasms/genetics , Neoplasms/pathology , RNA Interference , Signal Transduction/genetics , Sp3 Transcription Factor/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
This corrects the article DOI: 10.1038/ncomms14278.
ABSTRACT
Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Interferon-alpha/immunology , Interferon-beta/immunology , Thiazoles/pharmacology , Adaptive Immunity/drug effects , Animals , Antineoplastic Agents/chemical synthesis , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Brain Neoplasms/mortality , Cell Line, Tumor , Female , Gene Expression Regulation , Genetic Vectors/chemistry , Genetic Vectors/immunology , Glioblastoma/genetics , Glioblastoma/immunology , Glioblastoma/mortality , Humans , Immunity, Innate/drug effects , Immunologic Memory , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/immunology , Interferon-alpha/genetics , Interferon-alpha/pharmacology , Interferon-beta/genetics , Interferon-beta/pharmacology , Mice , Poly I-C/pharmacology , Signal Transduction , Survival Analysis , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Thiazoles/chemical synthesis , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/pharmacology , Vesiculovirus/genetics , Vesiculovirus/immunology , Xenograft Model Antitumor AssaysABSTRACT
Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe "cytokine storm." Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-ß), tumor necrosis factor alpha (TNF-α) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.