Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression
Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/7/1825 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Alexandros Papalampros Michail Vailas Konstantinos Ntostoglou Maria Lopez Chiloeches Stratigoula Sakellariou Niki V. Chouliari Menelaos G. Samaras Paraskevi D. Veltsista Sofia D. P. Theodorou Aggelos T. Margetis Anna Bergonzini Lysandros Karydakis Natasha Hasemaki Sophia Havaki Ioannis I. Moustakas Antonios Chatzigeorgiou Timokratis Karamitros Eleni Patsea Christos Kittas Andreas C. Lazaris Evangelos Felekouras Vassilis G. Gorgoulis Teresa Frisan Ioannis S. Pateras |
| spellingShingle |
Alexandros Papalampros Michail Vailas Konstantinos Ntostoglou Maria Lopez Chiloeches Stratigoula Sakellariou Niki V. Chouliari Menelaos G. Samaras Paraskevi D. Veltsista Sofia D. P. Theodorou Aggelos T. Margetis Anna Bergonzini Lysandros Karydakis Natasha Hasemaki Sophia Havaki Ioannis I. Moustakas Antonios Chatzigeorgiou Timokratis Karamitros Eleni Patsea Christos Kittas Andreas C. Lazaris Evangelos Felekouras Vassilis G. Gorgoulis Teresa Frisan Ioannis S. Pateras Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression Cancers pancreatic ductal adenocarcinoma spatial heterogeneity draining lymph nodes tumor microenvironment T cell exhaustion T cell senescence |
| author_facet |
Alexandros Papalampros Michail Vailas Konstantinos Ntostoglou Maria Lopez Chiloeches Stratigoula Sakellariou Niki V. Chouliari Menelaos G. Samaras Paraskevi D. Veltsista Sofia D. P. Theodorou Aggelos T. Margetis Anna Bergonzini Lysandros Karydakis Natasha Hasemaki Sophia Havaki Ioannis I. Moustakas Antonios Chatzigeorgiou Timokratis Karamitros Eleni Patsea Christos Kittas Andreas C. Lazaris Evangelos Felekouras Vassilis G. Gorgoulis Teresa Frisan Ioannis S. Pateras |
| author_sort |
Alexandros Papalampros |
| title |
Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression |
| title_short |
Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression |
| title_full |
Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression |
| title_fullStr |
Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression |
| title_full_unstemmed |
Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression |
| title_sort |
unique spatial immune profiling in pancreatic ductal adenocarcinoma with enrichment of exhausted and senescent t cells and diffused cd47-sirpα expression |
| publisher |
MDPI AG |
| series |
Cancers |
| issn |
2072-6694 |
| publishDate |
2020-07-01 |
| description |
Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities. |
| topic |
pancreatic ductal adenocarcinoma spatial heterogeneity draining lymph nodes tumor microenvironment T cell exhaustion T cell senescence |
| url |
https://www.mdpi.com/2072-6694/12/7/1825 |
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doaj-dfc91d009a644ed58f1a7b73b051ec602020-11-25T03:16:41ZengMDPI AGCancers2072-66942020-07-01121825182510.3390/cancers12071825Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα ExpressionAlexandros Papalampros0Michail Vailas1Konstantinos Ntostoglou2Maria Lopez Chiloeches3Stratigoula Sakellariou4Niki V. Chouliari5Menelaos G. Samaras6Paraskevi D. Veltsista7Sofia D. P. Theodorou8Aggelos T. Margetis9Anna Bergonzini10Lysandros Karydakis11Natasha Hasemaki12Sophia Havaki13Ioannis I. Moustakas14Antonios Chatzigeorgiou15Timokratis Karamitros16Eleni Patsea17Christos Kittas18Andreas C. Lazaris19Evangelos Felekouras20Vassilis G. Gorgoulis21Teresa Frisan22Ioannis S. Pateras23First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceFirst Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Molecular Biology, Umeå University, 90187 Umeå, SwedenFirst Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Molecular Biology, Umeå University, 90187 Umeå, SwedenFirst Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceFirst Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, GreeceBioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, GreeceDepartment of Pathology, Metropolitan General Hospital of Athens, 15562 Cholargos, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceFirst Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceFirst Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Molecular Biology, Umeå University, 90187 Umeå, SwedenMolecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceBackground: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.https://www.mdpi.com/2072-6694/12/7/1825pancreatic ductal adenocarcinomaspatial heterogeneitydraining lymph nodestumor microenvironmentT cell exhaustionT cell senescence |