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ID: 84
Cytokine 76 (2015) 61–65
Contents lists available at ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Invited symposia lectures ID: 177 Pathogen recognition and STING signaling
ID: 84 Innate immune responses in the regulation of tumor development
Glen Barber, Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, USA
Tadatsugu Taniguchi, Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, Japan
We have recently reported that STING (stimulator of interferon genes) is essential for controlling Toll-Like Receptor (TLR)-independent, cytosolic DNA-mediated innate immune signaling. Accordingly, STING appears essential for protecting the host against lethal disease following infection by pathogens such as HSV1. Such cellular DNA sensors may also play a key role in triggering inflammation aggravated autoimmune diseases. Autoimmune diseases such as Aicardi-Goutieres syndrome (AGS) are characterized by the overproduction of cytokines such as type I interferon (IFN) suggesting that stimulation of host innate immune responses, speculatively by chronic infection or self-nucleic acids, play a role in the manifestation of these diseases. It is known that mice lacking DNAse II die during embryonic development through comparable inflammatory disease since phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensors are activated resulting in the production of a variety of cytokines including type I IFN. However, we have found that STING controls innate immune signaling events that facilitate such events. DNase II-dependent autoimmune embryonic lethality was rescued by loss of STING function and polyarthritis completely prevented since cytosolic DNA failed to robustly trigger cytokine production through STING controlled signaling pathways. Consequently, loss of STING expression similarly alleviated Trex-1-dependent lethal inflammatory myocarditis is mice, a model for AGS, speculatively caused by endogenous self DNA. Our data provides molecular insight into the causes of DNA-mediated inflammation-dependent autoimmune disorders as well as inflammation driven cancer and affords a new target that could plausibly be therapeutically controlled, to help prevent such diseases.
When we initiated our studies on the molecular characterization of cytokines, namely type I interferons and interleukins, the conventional wisdom was that they are molecules secreted upon induction of gene transcription and translation by variety of stimuli. It was in this context that we also discovered a gene family for transcription factors, termed interferon regulatory factors (IRFs). IRFs have become a large focus in terms of their contribution in immunity and oncogenesis. In recent years, we focused our study on a new class of cytokine-like molecule, Highmobility group box protein 1 (HMGB1) that function in and out of the cell exerting seemingly unrelated biological activities. We present recent data showing the critical modifications of HMGB1 for its versatile functions, in particular, for the regulation of inflammation and tumor development. We also present recent results that show for how Dectin family of innate receptors contributes to anti-tumor responses, in which IRF5 activation is involved in part. The series of these finding will also be discussed in terms of cancer therapy. http://dx.doi.org/10.1016/j.cyto.2015.08.023
ID: 155 Innate immune responses during acute and chronic hepatitis C virus infections Markus Heim, University Hospital Basel, Basel, Switzerland
http://dx.doi.org/10.1016/j.cyto.2015.08.021
The Inhibitor of Apoptosis (IAP) family members are important oncogenes overexpressed in many solid and blood cancers. We have recently found that innate immune stimulants such as oncolytic viruses, TLR agonists and vaccines can potently synergize with a class of IAP-antagonist drugs known as Smac mimetic compounds, or SMCs, in various models of cancer [Beug et al., Nature Biotechnology 32: 182–90, 2014]. SMCs target and cause the degradation of the cellular inhibitors of apoptosis, cIAP1 and cIAP2, to specifically sensitize tumor cells to death signals from the immune system such as TNFa or TRAIL. Both cIAP1 and cIAP2 are ubiquitin ligases, with overlapping functions, which mediate signaling by all members of the TNF superfamily. The proteasomal-mediated degradation of cIAP1 and cIAP2 by SMCs alter immune-mediated signaling of various pathways controlled by these IAPs. SMCs are currently in early phase cancer clinical trial development and are well tolerated but show limited efficacy as monotherapy. However, in combination with immune stimulants, SMCs potently induce the bystander killing of tumor cells, which is attributable to a type I IFN dependent production of the proinflammatory cytokines TNFa and TRAIL. The approach is extremely effective in eradicating orthotopic models of mouse solid and blood cancers, including breast, glioblastoma and multiple myeloma. We propose that Smac mimetics will greatly improve the efficacy of oncolytic virus, and other immunotherapies, in the clinic.
An estimated 70% of individuals infected with hepatitis C virus (HCV) develop chronic hepatitis (CHC) that can lead to cirrhosis and hepatocellular carcinoma. The innate immune system is central to host-virus interactions during the entire natural course of the disease. The viral escape mechanisms that result in persistent infections are poorly understood. In vitro, The HCV NS3/4A protease efficiently cleaves and inactivates two important signaling molecules in the sensory pathways that react to HCV pathogen associated molecular patterns (PAMPs) to induce interferons (IFNs), i.e. mitochondrial anti-viral signaling protein (MAVS) and Toll-IL-1 receptor domaincontaining adaptor inducing IFN-b (TRIF). Despite this well documented viral escape mechanism, in vivo the innate immune system reacts to HCV within the first days after infection by inducing a strong IFN type I/III response. After 4–8 weeks, HCV specific T cells are recruited to the liver. IFN-c stimulated genes get strongly expressed in the liver. In about 30% of patients the virus is eliminated during the acute phase of the infection by T cell mediated anti-viral mechanisms. In the remaining 70% of patients, HCV persists for decades. During this phase, T cell derived IFN-c cannot be detected any more in liver biopsies. Instead, in about half of the patients, hundreds of type I or III IFN stimulated genes become again strongly expressed. However, this innate immune reaction is ineffective against HCV. Moreover, patients with constitutive IFN stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-a (pegIFN-aÞ and ribavirin. The viral escape mechanisms that protect HCV from IFN mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cells with refractory IFN signal transduction pathways or to cell compartments that are not accessible to anti-viral IFN stimulated effector systems. Recently, genetic variations in the IFN-k4 gene locus were found to be strongly associated to spontaneous clearance of HCV and to response to treatment with pegIFN-a and ribavirin. The finding supports a central role of the innate immune in host-viral interactions. The signaling pathways and cellular interactions that link genetic variants of IFN-k4 with immune answers to HCV remain to be elucidated.
http://dx.doi.org/10.1016/j.cyto.2015.08.022
http://dx.doi.org/10.1016/j.cyto.2015.08.024
ID: 261 Smac mimetics combined with innate immune stimuli: new tools to kill tumor cells Robert G. Korneluk, Children’s Hospital of Eastern Ontario Research Institute, Canada
Contents lists available at ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Invited symposia lectures ID: 177 Pathogen recognition and STING signaling
ID: 84 Innate immune responses in the regulation of tumor development
Glen Barber, Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, USA
Tadatsugu Taniguchi, Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, Japan
We have recently reported that STING (stimulator of interferon genes) is essential for controlling Toll-Like Receptor (TLR)-independent, cytosolic DNA-mediated innate immune signaling. Accordingly, STING appears essential for protecting the host against lethal disease following infection by pathogens such as HSV1. Such cellular DNA sensors may also play a key role in triggering inflammation aggravated autoimmune diseases. Autoimmune diseases such as Aicardi-Goutieres syndrome (AGS) are characterized by the overproduction of cytokines such as type I interferon (IFN) suggesting that stimulation of host innate immune responses, speculatively by chronic infection or self-nucleic acids, play a role in the manifestation of these diseases. It is known that mice lacking DNAse II die during embryonic development through comparable inflammatory disease since phagocytosed DNA from apoptotic cells cannot be adequately digested and intracellular host DNA sensors are activated resulting in the production of a variety of cytokines including type I IFN. However, we have found that STING controls innate immune signaling events that facilitate such events. DNase II-dependent autoimmune embryonic lethality was rescued by loss of STING function and polyarthritis completely prevented since cytosolic DNA failed to robustly trigger cytokine production through STING controlled signaling pathways. Consequently, loss of STING expression similarly alleviated Trex-1-dependent lethal inflammatory myocarditis is mice, a model for AGS, speculatively caused by endogenous self DNA. Our data provides molecular insight into the causes of DNA-mediated inflammation-dependent autoimmune disorders as well as inflammation driven cancer and affords a new target that could plausibly be therapeutically controlled, to help prevent such diseases.
When we initiated our studies on the molecular characterization of cytokines, namely type I interferons and interleukins, the conventional wisdom was that they are molecules secreted upon induction of gene transcription and translation by variety of stimuli. It was in this context that we also discovered a gene family for transcription factors, termed interferon regulatory factors (IRFs). IRFs have become a large focus in terms of their contribution in immunity and oncogenesis. In recent years, we focused our study on a new class of cytokine-like molecule, Highmobility group box protein 1 (HMGB1) that function in and out of the cell exerting seemingly unrelated biological activities. We present recent data showing the critical modifications of HMGB1 for its versatile functions, in particular, for the regulation of inflammation and tumor development. We also present recent results that show for how Dectin family of innate receptors contributes to anti-tumor responses, in which IRF5 activation is involved in part. The series of these finding will also be discussed in terms of cancer therapy. http://dx.doi.org/10.1016/j.cyto.2015.08.023
ID: 155 Innate immune responses during acute and chronic hepatitis C virus infections Markus Heim, University Hospital Basel, Basel, Switzerland
http://dx.doi.org/10.1016/j.cyto.2015.08.021
The Inhibitor of Apoptosis (IAP) family members are important oncogenes overexpressed in many solid and blood cancers. We have recently found that innate immune stimulants such as oncolytic viruses, TLR agonists and vaccines can potently synergize with a class of IAP-antagonist drugs known as Smac mimetic compounds, or SMCs, in various models of cancer [Beug et al., Nature Biotechnology 32: 182–90, 2014]. SMCs target and cause the degradation of the cellular inhibitors of apoptosis, cIAP1 and cIAP2, to specifically sensitize tumor cells to death signals from the immune system such as TNFa or TRAIL. Both cIAP1 and cIAP2 are ubiquitin ligases, with overlapping functions, which mediate signaling by all members of the TNF superfamily. The proteasomal-mediated degradation of cIAP1 and cIAP2 by SMCs alter immune-mediated signaling of various pathways controlled by these IAPs. SMCs are currently in early phase cancer clinical trial development and are well tolerated but show limited efficacy as monotherapy. However, in combination with immune stimulants, SMCs potently induce the bystander killing of tumor cells, which is attributable to a type I IFN dependent production of the proinflammatory cytokines TNFa and TRAIL. The approach is extremely effective in eradicating orthotopic models of mouse solid and blood cancers, including breast, glioblastoma and multiple myeloma. We propose that Smac mimetics will greatly improve the efficacy of oncolytic virus, and other immunotherapies, in the clinic.
An estimated 70% of individuals infected with hepatitis C virus (HCV) develop chronic hepatitis (CHC) that can lead to cirrhosis and hepatocellular carcinoma. The innate immune system is central to host-virus interactions during the entire natural course of the disease. The viral escape mechanisms that result in persistent infections are poorly understood. In vitro, The HCV NS3/4A protease efficiently cleaves and inactivates two important signaling molecules in the sensory pathways that react to HCV pathogen associated molecular patterns (PAMPs) to induce interferons (IFNs), i.e. mitochondrial anti-viral signaling protein (MAVS) and Toll-IL-1 receptor domaincontaining adaptor inducing IFN-b (TRIF). Despite this well documented viral escape mechanism, in vivo the innate immune system reacts to HCV within the first days after infection by inducing a strong IFN type I/III response. After 4–8 weeks, HCV specific T cells are recruited to the liver. IFN-c stimulated genes get strongly expressed in the liver. In about 30% of patients the virus is eliminated during the acute phase of the infection by T cell mediated anti-viral mechanisms. In the remaining 70% of patients, HCV persists for decades. During this phase, T cell derived IFN-c cannot be detected any more in liver biopsies. Instead, in about half of the patients, hundreds of type I or III IFN stimulated genes become again strongly expressed. However, this innate immune reaction is ineffective against HCV. Moreover, patients with constitutive IFN stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-a (pegIFN-aÞ and ribavirin. The viral escape mechanisms that protect HCV from IFN mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cells with refractory IFN signal transduction pathways or to cell compartments that are not accessible to anti-viral IFN stimulated effector systems. Recently, genetic variations in the IFN-k4 gene locus were found to be strongly associated to spontaneous clearance of HCV and to response to treatment with pegIFN-a and ribavirin. The finding supports a central role of the innate immune in host-viral interactions. The signaling pathways and cellular interactions that link genetic variants of IFN-k4 with immune answers to HCV remain to be elucidated.
http://dx.doi.org/10.1016/j.cyto.2015.08.022
http://dx.doi.org/10.1016/j.cyto.2015.08.024
ID: 261 Smac mimetics combined with innate immune stimuli: new tools to kill tumor cells Robert G. Korneluk, Children’s Hospital of Eastern Ontario Research Institute, Canada