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Article ; Online: 863 Identification and characterization of an immunodominant SARS-CoV-2-specific CD8 T cell response

Pia Kvistborg / Anastasia Gangaev

Journal for ImmunoTherapy of Cancer, Vol 8, Iss Suppl

2020 Volume 3

Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; covid19
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Imatinib Regulates

Huang, Wen-Kuan / Shi, Hao / Akçakaya, Pinar / Zeljic, Katarina / Gangaev, Anastasia / Caramuta, Stefano / Yeh, Chun-Nan / Bränström, Robert / Larsson, Catharina / Lui, Weng-Onn

International journal of molecular sciences

2021 Volume 22, Issue 19

Abstract: Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that ... ...

Abstract	Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Down-Regulation/drug effects ; Electron Transport Complex II/metabolism ; Gastrointestinal Neoplasms/drug therapy ; Gastrointestinal Neoplasms/genetics ; Gastrointestinal Neoplasms/metabolism ; Gastrointestinal Neoplasms/pathology ; Gastrointestinal Stromal Tumors/drug therapy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/metabolism ; Gastrointestinal Stromal Tumors/pathology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Imatinib Mesylate/pharmacology ; Imatinib Mesylate/therapeutic use ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Mitochondria/drug effects ; Mitochondria/enzymology ; Oxidative Phosphorylation/drug effects ; RNA, Messenger/genetics ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Transfection
Chemical Substances	Antineoplastic Agents ; MIRN483 microRNA, human ; MicroRNAs ; RNA, Messenger ; respiratory complex II ; Imatinib Mesylate (8A1O1M485B) ; Electron Transport Complex II (EC 1.3.5.1)
Language	English
Publishing date	2021-09-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms221910600
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Article ; Online: Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA peptidomics.

Nagler, Adi / Kalaora, Shelly / Barbolin, Chaya / Gangaev, Anastasia / Ketelaars, Steven L C / Alon, Michal / Pai, Joy / Benedek, Gil / Yahalom-Ronen, Yfat / Erez, Noam / Greenberg, Polina / Yagel, Gal / Peri, Aviyah / Levin, Yishai / Satpathy, Ansuman T / Bar-Haim, Erez / Paran, Nir / Kvistborg, Pia / Samuels, Yardena

Cell reports

2021 Volume 35, Issue 13, Page(s) 109305

Abstract: The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA ...

Abstract	The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes.
MeSH term(s)	Antigen Presentation ; Antigens, Viral/immunology ; Antigens, Viral/metabolism ; COVID-19/immunology ; COVID-19/virology ; COVID-19 Vaccines ; Cell Line ; Epitopes, T-Lymphocyte/immunology ; HEK293 Cells ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class II/immunology ; Humans ; Peptides/immunology ; Peptidomimetics ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; T-Lymphocytes
Chemical Substances	Antigens, Viral ; COVID-19 Vaccines ; Epitopes, T-Lymphocyte ; Histocompatibility Antigens Class I ; Histocompatibility Antigens Class II ; Peptides ; Peptidomimetics
Language	English
Publishing date	2021-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109305
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Article ; Online: Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors

Wen-Kuan Huang / Hao Shi / Pinar Akçakaya / Katarina Zeljic / Anastasia Gangaev / Stefano Caramuta / Chun-Nan Yeh / Robert Bränström / Catharina Larsson / Weng-Onn Lui

International Journal of Molecular Sciences, Vol 22, Iss 10600, p

2021 Volume 10600

Abstract	Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.
Keywords	gastrointestinal stromal tumor (GIST) ; imatinib ; microRNA ; oxidative phosphorylation ; miR-483 ; succinate dehydrogenase B ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	500
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response.

Gangaev, Anastasia / Rozeman, Elisa A / Rohaan, Maartje W / Isaeva, Olga I / Philips, Daisy / Patiwael, Sanne / van den Berg, Joost H / Ribas, Antoni / Schadendorf, Dirk / Schilling, Bastian / Schumacher, Ton N / Blank, Christian U / Haanen, John B A G / Kvistborg, Pia

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 43

Abstract: Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it ... ...

Abstract	Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If the activation of circulating, tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses toward 71 melanoma-associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactive CD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. Based on these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CTLA-4 Antigen/antagonists & inhibitors ; Cohort Studies ; Epitopes, T-Lymphocyte/blood ; Epitopes, T-Lymphocyte/immunology ; Female ; Hepatitis A Virus Cellular Receptor 2/blood ; Hepatitis A Virus Cellular Receptor 2/immunology ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; In Vitro Techniques ; Kinetics ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Male ; Melanoma/drug therapy ; Melanoma/immunology ; Melanoma-Specific Antigens/blood ; Melanoma-Specific Antigens/immunology ; Middle Aged ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Receptors, Antigen, T-Cell, alpha-beta/blood ; Receptors, Antigen, T-Cell, alpha-beta/immunology ; Receptors, CXCR5/blood ; Receptors, CXCR5/immunology
Chemical Substances	CTLA-4 Antigen ; CTLA4 protein, human ; CXCR5 protein, human ; Epitopes, T-Lymphocyte ; HAVCR2 protein, human ; Hepatitis A Virus Cellular Receptor 2 ; Immune Checkpoint Inhibitors ; Melanoma-Specific Antigens ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Receptors, Antigen, T-Cell, alpha-beta ; Receptors, CXCR5
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2102849118
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Article ; Online: Identification and characterization of a SARS-CoV-2 specific CD8

Nature communications

2021 Volume 12, Issue 1, Page(s) 2593

Abstract: The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by ... ...

Abstract	The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alleles ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; COVID-19/immunology ; COVID-19/pathology ; Epitopes, T-Lymphocyte/immunology ; Female ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Humans ; Immunodominant Epitopes/chemistry ; Immunodominant Epitopes/immunology ; Immunologic Memory ; Lymphocyte Activation ; Male ; Middle Aged ; Polyproteins/immunology ; SARS-CoV-2/immunology ; Viral Proteins/immunology
Chemical Substances	Epitopes, T-Lymphocyte ; Histocompatibility Antigens Class I ; Immunodominant Epitopes ; ORF1ab polyprotein, SARS-CoV-2 ; Polyproteins ; Viral Proteins
Language	English
Publishing date	2021-05-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-22811-y
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Article ; Online: Alternative trafficking of Weibel-Palade body proteins in CRISPR/Cas9-engineered von Willebrand factor-deficient blood outgrowth endothelial cells.

Schillemans, Maaike / Kat, Marije / Westeneng, Jurjen / Gangaev, Anastasia / Hofman, Menno / Nota, Benjamin / van Alphen, Floris P J / de Boer, Martin / van den Biggelaar, Maartje / Margadant, Coert / Voorberg, Jan / Bierings, Ruben

Research and practice in thrombosis and haemostasis

2019 Volume 3, Issue 4, Page(s) 718–732

Abstract: Background: Synthesis of the hemostatic protein von Willebrand factor (VWF) drives formation of endothelial storage organelles called Weibel-Palade bodies (WPBs). In the absence of VWF, angiogenic and inflammatory mediators that are costored in WPBs are ...

Abstract	Background: Synthesis of the hemostatic protein von Willebrand factor (VWF) drives formation of endothelial storage organelles called Weibel-Palade bodies (WPBs). In the absence of VWF, angiogenic and inflammatory mediators that are costored in WPBs are subject to alternative trafficking routes. In patients with von Willebrand disease (VWD), partial or complete absence of VWF/WPBs may lead to additional bleeding complications, such as angiodysplasia. Studies addressing the role of VWF using VWD patient-derived blood outgrowth endothelial cells (BOECs) have reported conflicting results due to the intrinsic heterogeneity of patient-derived BOECs. Objective: To generate a VWF-deficient endothelial cell model using clustered regularly interspaced short palindromic repeats (CRISPR) genome engineering of blood outgrowth endothelial cells. Methods: We used CRISPR/CRISPR-associated protein 9 editing in single-donor cord blood-derived BOECs (cbBOECs) to generate clonal Results: Two Conclusions: CRISPR editing of
Language	English
Publishing date	2019-08-01
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1002/rth2.12242
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Article ; Online: Identification and characterization of a SARS-CoV-2 specific CD8+ T cell response with immunodominant features

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 14

Abstract: Many viral antigens have been identified in patients with COVID-19 patients, but which of these result in meaningful immune responses is unclear. Here the authors identify a range of SARS-CoV-2 CD8+ T cell responses across patients including a response ... ...

Abstract	Many viral antigens have been identified in patients with COVID-19 patients, but which of these result in meaningful immune responses is unclear. Here the authors identify a range of SARS-CoV-2 CD8+ T cell responses across patients including a response targeting an epitope of ORF1ab with immunodominant properties.
Keywords	Science ; Q
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: miR-125a-5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors.

Huang, Wen-Kuan / Akçakaya, Pinar / Gangaev, Anastasia / Lee, Linkiat / Zeljic, Katarina / Hajeri, Praveensingh / Berglund, Erik / Ghaderi, Mehran / Åhlén, Jan / Bränström, Robert / Larsson, Catharina / Lui, Weng-Onn

Experimental cell research

2018 Volume 371, Issue 1, Page(s) 287–296

Abstract: The use of imatinib mesylate has greatly improved the clinical outcome for gastrointestinal stromal tumor (GIST) patients. However, imatinib resistance is still a major clinical challenge, and the molecular mechanisms are not fully understood. We have ... ...

Abstract	The use of imatinib mesylate has greatly improved the clinical outcome for gastrointestinal stromal tumor (GIST) patients. However, imatinib resistance is still a major clinical challenge, and the molecular mechanisms are not fully understood. We have previously shown that miR-125a-5p and its mRNA target PTPN18 modulate imatinib response in GIST cells. Herein, we evaluated phosphorylated FAK (pFAK) as a candidate downstream target of PTPN18 and the possible association of this regulation with imatinib resistance in GIST. FAK and pFAK expressions were evaluated in GIST882 cells transfected with short hairpin RNA or short interfering RNA targeting PTPN18 or miR-125a-5p mimic, imatinib-resistant GIST882R subclones and clinical samples using Western blot analyses. FAK phosphorylation was blocked using the FAK inhibitor 14 (FAKi) and the effects on cell viability and apoptosis were evaluated using WST-1 assay and cleaved PARP expression. Clinical associations of FAK and pFAK expression with imatinib resistance, KIT mutation and patient outcome were assessed by Fisher's exact test or log-rank test. Over-expression of miR-125a-5p and silencing of PTPN18 increased pFAK, but not FAK, expression in GIST cells. Higher pFAK expression was observed in the GIST882R subclones with acquired imatinib resistance compared to their imatinib-sensitive parental cells. Treatment with FAKi in imatinib-resistant GIST882R cells reduced cell viability and increased apoptosis upon imatinib treatment. Additionally, FAKi could rescue the imatinib resistance effect mediated by miR-125a-5p over-expression. In clinical samples, high FAK and pFAK expressions were associated with KIT mutation status, and high FAK expression was also associated with metastasis in GIST. Higher pFAK was found in cases with shorter overall survival. Our findings highlight an important role for miR-125a-5p regulation and its downstream target pFAK for imatinib resistance in GIST. pFAK and FAK may have prognostic values in GIST.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Focal Adhesion Kinase 1/genetics ; Focal Adhesion Kinase 1/metabolism ; Gastrointestinal Neoplasms/diagnosis ; Gastrointestinal Neoplasms/drug therapy ; Gastrointestinal Neoplasms/genetics ; Gastrointestinal Neoplasms/mortality ; Gastrointestinal Stromal Tumors/diagnosis ; Gastrointestinal Stromal Tumors/drug therapy ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/mortality ; Gene Expression Regulation, Neoplastic ; Humans ; Imatinib Mesylate/pharmacology ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Oligoribonucleotides/genetics ; Oligoribonucleotides/metabolism ; Phosphorylation ; Prognosis ; Protein Kinase Inhibitors/pharmacology ; Protein Tyrosine Phosphatases, Non-Receptor/antagonists & inhibitors ; Protein Tyrosine Phosphatases, Non-Receptor/genetics ; Protein Tyrosine Phosphatases, Non-Receptor/metabolism ; RNA, Messenger/antagonists & inhibitors ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Survival Analysis
Chemical Substances	Antineoplastic Agents ; MIRN125 microRNA, human ; MicroRNAs ; Oligoribonucleotides ; Protein Kinase Inhibitors ; RNA, Messenger ; RNA, Small Interfering ; STAT3 Transcription Factor ; STAT3 protein, human ; Imatinib Mesylate (8A1O1M485B) ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; PTK2 protein, human (EC 2.7.10.2) ; PTPN18 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatases, Non-Receptor (EC 3.1.3.48)
Language	English
Publishing date	2018-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2018.08.028
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Zs.A 563: Show issues

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Article ; Online: Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA peptidomics

Adi Nagler / Shelly Kalaora / Chaya Barbolin / Anastasia Gangaev / Steven L.C. Ketelaars / Michal Alon / Joy Pai / Gil Benedek / Yfat Yahalom-Ronen / Noam Erez / Polina Greenberg / Gal Yagel / Aviyah Peri / Yishai Levin / Ansuman T. Satpathy / Erez Bar-Haim / Nir Paran / Pia Kvistborg / Yardena Samuels

Cell Reports, Vol 35, Iss 13, Pp 109305- (2021)

2021

Abstract: Summary: The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. ... ...

Abstract	Summary: The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes.
Keywords	SARS-CoV-2 ; HLA ; Peptides ; Peptidomics ; out-of-frame-ORFs ; immuno-reactive ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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