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Article

Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression

1
First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
2
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
3
Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden
4
First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Oncology, School of Medical Sciences, Vrije Universiteit Amsterdam, De Boelelaan, 1117 Amsterdam, The Netherlands
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Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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Department of Pathology, Metropolitan General Hospital of Athens, 15562 Cholargos, Greece
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Faculty of Biology, Medicine and Health Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester M20-4GJ, UK
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Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, 11527 Athens, Greece
12
Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
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Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
Equal contribution.
Senior authors.
Cancers 2020, 12(7), 1825; https://doi.org/10.3390/cancers12071825
Received: 23 May 2020 / Revised: 1 July 2020 / Accepted: 2 July 2020 / Published: 7 July 2020
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. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; spatial heterogeneity; draining lymph nodes; tumor microenvironment; T cell exhaustion; T cell senescence; neoadjuvant chemotherapy; macrophage checkpoint; CD47; signal regulatory protein alpha (SIRPα) pancreatic ductal adenocarcinoma; spatial heterogeneity; draining lymph nodes; tumor microenvironment; T cell exhaustion; T cell senescence; neoadjuvant chemotherapy; macrophage checkpoint; CD47; signal regulatory protein alpha (SIRPα)
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MDPI and ACS Style

Papalampros, A.; Vailas, M.; Ntostoglou, K.; Chiloeches, M.L.; Sakellariou, S.; Chouliari, N.V.; Samaras, M.G.; Veltsista, P.D.; Theodorou, S.D.P.; Margetis, A.T.; Bergonzini, A.; Karydakis, L.; Hasemaki, N.; Havaki, S.; Moustakas, I.I.; Chatzigeorgiou, A.; Karamitros, T.; Patsea, E.; Kittas, C.; Lazaris, A.C.; Felekouras, E.; Gorgoulis, V.G.; Frisan, T.; Pateras, I.S. Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression. Cancers 2020, 12, 1825. https://doi.org/10.3390/cancers12071825

AMA Style

Papalampros A, Vailas M, Ntostoglou K, Chiloeches ML, Sakellariou S, Chouliari NV, Samaras MG, Veltsista PD, Theodorou SDP, Margetis AT, Bergonzini A, Karydakis L, Hasemaki N, Havaki S, Moustakas II, Chatzigeorgiou A, Karamitros T, Patsea E, Kittas C, Lazaris AC, Felekouras E, Gorgoulis VG, Frisan T, Pateras IS. Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression. Cancers. 2020; 12(7):1825. https://doi.org/10.3390/cancers12071825

Chicago/Turabian Style

Papalampros, Alexandros, Michail Vailas, Konstantinos Ntostoglou, Maria L. 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, and Ioannis S. Pateras 2020. "Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression" Cancers 12, no. 7: 1825. https://doi.org/10.3390/cancers12071825

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