The Experts below are selected from a list of 30138 Experts worldwide ranked by ideXlab platform
Marjolein Kikkert - One of the best experts on this subject based on the ideXlab platform.
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innate Immune Evasion by human respiratory rna viruses
Journal of Innate Immunity, 2020Co-Authors: Marjolein KikkertAbstract:The impact of respiratory virus infections on the health of children and adults can be very significant. Yet, in contrast to most other childhood infections as well as other viral and bacterial diseases, prophylactic vaccines or effective antiviral treatments against viral respiratory infections are either still not available, or provide only limited protection. Given the widespread prevalence, a general lack of natural sterilizing immunity, and/or high morbidity and lethality rates of diseases caused by influenza, respiratory syncytial virus, coronaviruses, and rhinoviruses, this difficult situation is a genuine societal challenge. A thorough understanding of the virus-host interactions during these respiratory infections will most probably be pivotal to ultimately meet these challenges. This review attempts to provide a comparative overview of the knowledge about an important part of the interaction between respiratory viruses and their host: the arms race between host innate immunity and viral innate Immune Evasion. Many, if not all, viruses, including the respiratory viruses listed above, suppress innate Immune responses to gain a window of opportunity for efficient virus replication and setting-up of the infection. The consequences for the host's Immune response are that it is often incomplete, delayed or diminished, or displays overly strong induction (after the delay) that may cause tissue damage. The affected innate Immune response also impacts subsequent adaptive responses, and therefore viral innate Immune Evasion often undermines fully protective immunity. In this review, innate Immune responses relevant for respiratory viruses with an RNA genome will briefly be summarized, and viral innate Immune Evasion based on shielding viral RNA species away from cellular innate Immune sensors will be discussed from different angles. Subsequently, viral enzymatic activities that suppress innate Immune responses will be discussed, including activities causing host shut-off and manipulation of stress granule formation. Furthermore, viral protease-mediated Immune Evasion and viral manipulation of the ubiquitin system will be addressed. Finally, perspectives for use of the reviewed knowledge for the development of novel antiviral strategies will be sketched.
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Viral Innate Immune Evasion and the Pathogenesis of Emerging RNA Virus Infections
Viruses, 2019Co-Authors: Tessa Nelemans, Marjolein KikkertAbstract:Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate Immune system and, in particular, the interferon response form the important first line of defence against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate Immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate Immune Evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate Immune Evasion on the pathology caused by viral infections is less prevalent in the literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, antagonizing the Immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host Immune Evasion in the pathogenesis of emerging coronaviruses, alphaviruses and flaviviruses.
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Viral Innate Immune Evasion and the Pathogenesis of Emerging RNA Virus Infections
2019Co-Authors: Tessa Nelemans, Marjolein KikkertAbstract:Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate Immune system and in particular the interferon response form the important first line of defense against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate Immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate Immune Evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate Immune Evasion on the pathology caused by the viral infection is less prevalent in literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, the influence of antagonizing the Immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host Immune Evasion in the pathogenesis of emerging viruses belonging to the coronaviruses, alphaviruses and flaviviruses.
William A Freedpastor - One of the best experts on this subject based on the ideXlab platform.
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the cd155 tigit axis promotes and maintains Immune Evasion in neoantigen expressing pancreatic cancer
Cancer Cell, 2021Co-Authors: William A Freedpastor, Laurens J Lambert, Nimisha B Pattada, Arjun Bhutkar, George Eng, Kim L Mercer, Zackery A Ely, Ana P GarciaAbstract:Summary The CD155/TIGIT axis can be co-opted during Immune Evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and Immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote Immune Evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining Immune Evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
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the cd155 tigit axis promotes and maintains Immune Evasion in neoantigen expressing pancreatic cancer
2020Co-Authors: William A Freedpastor, Laurens J Lambert, Zackery Ely, Nimisha B Pattada, Arjun Bhutkar, George Eng, Kim L Mercer, Ana P Garcia, Lin Lin, William M RideoutAbstract:The CD155/TIGIT axis can be co-opted during Immune Evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and Immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using two novel preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, which are similar to tumor-infiltrating lymphocytes of human PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote Immune Evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical to maintain Immune Evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
Pauline L. Pfuderer - One of the best experts on this subject based on the ideXlab platform.
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High endothelial venules are associated with microsatellite instability, hereditary background and Immune Evasion in colorectal cancer
British Journal of Cancer, 2019Co-Authors: Pauline L. Pfuderer, Matthias Kloor, Ann Ager, Alexej Ballhausen, Florian Seidler, Hans-jürgen Stark, Niels Grabe, Ian M. Frayling, Magnus Knebel Doeberitz, Aysel AhadovaAbstract:Background Microsatellite-unstable (MSI) tumours show a high load of mutational neo antigens, as a consequence of DNA mismatch repair deficiency. Consequently, MSI tumours commonly present with dense Immune infiltration and develop Immune Evasion mechanisms. Whether improved lymphocyte recruitment contributes to the pronounced Immune infiltration in MSI tumours is unknown. We analysed the density of high endothelial venules (HEV) and postcapillary blood vessels specialised for lymphocyte trafficking, in MSI colorectal cancers (CRC). Methods HEV density was determined by immunohistochemical staining of FFPE tissue sections from MSI ( n = 48) and microsatellite-stable (MSS, n = 35) CRCs. Associations with clinical and pathological variables were analysed. Results We found elevated HEV densities in MSI compared with MSS CRCs (median 0.049 vs 0.000 counts/mm^2, respectively, p = 0.0002), with the highest densities in Lynch syndrome MSI CRCs. Dramatically elevated HEV densities were observed in B2M- mutant Lynch syndrome CRCs, pointing towards a link between lymphocyte recruitment and Immune Evasion (median 0.485 vs 0.0885 counts/mm^2 in B2M -wild-type tumours, p = 0.0237). Conclusions Our findings for the first time indicate a significant contribution of lymphocyte trafficking in Immune responses against MSI CRC, particularly in the context of Lynch syndrome. High HEV densities in B2M -mutant tumours underline the significance of immunoediting during tumour evolution.
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high endothelial venules are associated with microsatellite instability hereditary background and Immune Evasion in colorectal cancer
British Journal of Cancer, 2019Co-Authors: Pauline L. Pfuderer, Alexej Ballhausen, Florian Seidler, Hans-jürgen Stark, Niels Grabe, Ian M. FraylingAbstract:Microsatellite-unstable (MSI) tumours show a high load of mutational neoantigens, as a consequence of DNA mismatch repair deficiency. Consequently, MSI tumours commonly present with dense Immune infiltration and develop Immune Evasion mechanisms. Whether improved lymphocyte recruitment contributes to the pronounced Immune infiltration in MSI tumours is unknown. We analysed the density of high endothelial venules (HEV) and postcapillary blood vessels specialised for lymphocyte trafficking, in MSI colorectal cancers (CRC). HEV density was determined by immunohistochemical staining of FFPE tissue sections from MSI (n = 48) and microsatellite-stable (MSS, n = 35) CRCs. Associations with clinical and pathological variables were analysed. We found elevated HEV densities in MSI compared with MSS CRCs (median 0.049 vs 0.000 counts/mm2, respectively, p = 0.0002), with the highest densities in Lynch syndrome MSI CRCs. Dramatically elevated HEV densities were observed in B2M-mutant Lynch syndrome CRCs, pointing towards a link between lymphocyte recruitment and Immune Evasion (median 0.485 vs 0.0885 counts/mm2 in B2M-wild-type tumours, p = 0.0237). Our findings for the first time indicate a significant contribution of lymphocyte trafficking in Immune responses against MSI CRC, particularly in the context of Lynch syndrome. High HEV densities in B2M-mutant tumours underline the significance of immunoediting during tumour evolution.
Ana P Garcia - One of the best experts on this subject based on the ideXlab platform.
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the cd155 tigit axis promotes and maintains Immune Evasion in neoantigen expressing pancreatic cancer
Cancer Cell, 2021Co-Authors: William A Freedpastor, Laurens J Lambert, Nimisha B Pattada, Arjun Bhutkar, George Eng, Kim L Mercer, Zackery A Ely, Ana P GarciaAbstract:Summary The CD155/TIGIT axis can be co-opted during Immune Evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and Immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote Immune Evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining Immune Evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
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the cd155 tigit axis promotes and maintains Immune Evasion in neoantigen expressing pancreatic cancer
2020Co-Authors: William A Freedpastor, Laurens J Lambert, Zackery Ely, Nimisha B Pattada, Arjun Bhutkar, George Eng, Kim L Mercer, Ana P Garcia, Lin Lin, William M RideoutAbstract:The CD155/TIGIT axis can be co-opted during Immune Evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and Immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using two novel preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, which are similar to tumor-infiltrating lymphocytes of human PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote Immune Evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical to maintain Immune Evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
George Eng - One of the best experts on this subject based on the ideXlab platform.
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the cd155 tigit axis promotes and maintains Immune Evasion in neoantigen expressing pancreatic cancer
Cancer Cell, 2021Co-Authors: William A Freedpastor, Laurens J Lambert, Nimisha B Pattada, Arjun Bhutkar, George Eng, Kim L Mercer, Zackery A Ely, Ana P GarciaAbstract:Summary The CD155/TIGIT axis can be co-opted during Immune Evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and Immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote Immune Evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining Immune Evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
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the cd155 tigit axis promotes and maintains Immune Evasion in neoantigen expressing pancreatic cancer
2020Co-Authors: William A Freedpastor, Laurens J Lambert, Zackery Ely, Nimisha B Pattada, Arjun Bhutkar, George Eng, Kim L Mercer, Ana P Garcia, Lin Lin, William M RideoutAbstract:The CD155/TIGIT axis can be co-opted during Immune Evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and Immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using two novel preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, which are similar to tumor-infiltrating lymphocytes of human PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote Immune Evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical to maintain Immune Evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
