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Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in need of effective (immuno)therapeutic treatment strategies. For the optimal application and development of cancer immunotherapies, a comprehensive understanding of local and systemic immune profiles in patients with...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260840/ https://www.ncbi.nlm.nih.gov/pubmed/35793870 http://dx.doi.org/10.1136/jitc-2022-004638 |
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author | Brouwer, Thomas P de Vries, Natasja L Abdelaal, Tamim Krog, Ricki T Li, Zheng Ruano, Dina Fariña, Arantza Lelieveldt, Boudewijn P F Morreau, Hans Bonsing, Bert A Vahrmeijer, Alexander L Koning, Frits de Miranda, Noel F C C |
author_facet | Brouwer, Thomas P de Vries, Natasja L Abdelaal, Tamim Krog, Ricki T Li, Zheng Ruano, Dina Fariña, Arantza Lelieveldt, Boudewijn P F Morreau, Hans Bonsing, Bert A Vahrmeijer, Alexander L Koning, Frits de Miranda, Noel F C C |
author_sort | Brouwer, Thomas P |
collection | PubMed |
description | BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in need of effective (immuno)therapeutic treatment strategies. For the optimal application and development of cancer immunotherapies, a comprehensive understanding of local and systemic immune profiles in patients with PDAC is required. Here, our goal was to decipher the interplay between local and systemic immune profiles in treatment-naïve patients with PDAC. METHODS: The immune composition of PDAC, matched non-malignant pancreatic tissue, regional lymph nodes, spleen, portal vein blood, and peripheral blood samples (collected before and after surgery) from 11 patients with PDAC was assessed by measuring 41 immune cell markers by single-cell mass cytometry. Furthermore, the activation potential of tumor-infiltrating lymphocytes as determined by their ability to produce cytokines was investigated by flow cytometry. In addition, the spatial localization of tumor-infiltrating innate lymphocytes in the tumor microenvironment was confirmed by multispectral immunofluorescence. RESULTS: We found that CD103(+)CD8(+) T cells with cytotoxic potential are infrequent in the PDAC immune microenvironment and lack the expression of activation markers and checkpoint blockade molecule programmed cell death protein-1 (PD-1). In contrast, PDAC tissues showed a remarkable increased relative frequency of B cells and regulatory T cells as compared with non-malignant pancreatic tissues. Besides, a previously unappreciated innate lymphocyte cell (ILC) population (CD127(–)CD103(+)CD39(+)CD45RO(+) ILC1-like) was discovered in PDAC tissues. Strikingly, the increased relative frequency of B cells and regulatory T cells in pancreatic cancer samples was reflected in matched portal vein blood samples but not in peripheral blood, suggesting a regional enrichment of immune cells that infiltrate the PDAC microenvironment. After surgery, decreased frequencies of myeloid dendritic cells were found in peripheral blood. CONCLUSIONS: Our work demonstrates an immunosuppressive landscape in PDAC tissues, generally deprived of cytotoxic T cells and enriched in regulatory T cells and B cells. The antitumor potential of ILC1-like cells in PDAC may be exploited in a therapeutic setting. Importantly, immune profiles detected in blood isolated from the portal vein reflected the immune cell composition of the PDAC microenvironment, suggesting that this anatomical location could be a source of tumor-associated immune cell subsets. |
format | Online Article Text |
id | pubmed-9260840 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-92608402022-07-28 Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry Brouwer, Thomas P de Vries, Natasja L Abdelaal, Tamim Krog, Ricki T Li, Zheng Ruano, Dina Fariña, Arantza Lelieveldt, Boudewijn P F Morreau, Hans Bonsing, Bert A Vahrmeijer, Alexander L Koning, Frits de Miranda, Noel F C C J Immunother Cancer Basic Tumor Immunology BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in need of effective (immuno)therapeutic treatment strategies. For the optimal application and development of cancer immunotherapies, a comprehensive understanding of local and systemic immune profiles in patients with PDAC is required. Here, our goal was to decipher the interplay between local and systemic immune profiles in treatment-naïve patients with PDAC. METHODS: The immune composition of PDAC, matched non-malignant pancreatic tissue, regional lymph nodes, spleen, portal vein blood, and peripheral blood samples (collected before and after surgery) from 11 patients with PDAC was assessed by measuring 41 immune cell markers by single-cell mass cytometry. Furthermore, the activation potential of tumor-infiltrating lymphocytes as determined by their ability to produce cytokines was investigated by flow cytometry. In addition, the spatial localization of tumor-infiltrating innate lymphocytes in the tumor microenvironment was confirmed by multispectral immunofluorescence. RESULTS: We found that CD103(+)CD8(+) T cells with cytotoxic potential are infrequent in the PDAC immune microenvironment and lack the expression of activation markers and checkpoint blockade molecule programmed cell death protein-1 (PD-1). In contrast, PDAC tissues showed a remarkable increased relative frequency of B cells and regulatory T cells as compared with non-malignant pancreatic tissues. Besides, a previously unappreciated innate lymphocyte cell (ILC) population (CD127(–)CD103(+)CD39(+)CD45RO(+) ILC1-like) was discovered in PDAC tissues. Strikingly, the increased relative frequency of B cells and regulatory T cells in pancreatic cancer samples was reflected in matched portal vein blood samples but not in peripheral blood, suggesting a regional enrichment of immune cells that infiltrate the PDAC microenvironment. After surgery, decreased frequencies of myeloid dendritic cells were found in peripheral blood. CONCLUSIONS: Our work demonstrates an immunosuppressive landscape in PDAC tissues, generally deprived of cytotoxic T cells and enriched in regulatory T cells and B cells. The antitumor potential of ILC1-like cells in PDAC may be exploited in a therapeutic setting. Importantly, immune profiles detected in blood isolated from the portal vein reflected the immune cell composition of the PDAC microenvironment, suggesting that this anatomical location could be a source of tumor-associated immune cell subsets. BMJ Publishing Group 2022-07-06 /pmc/articles/PMC9260840/ /pubmed/35793870 http://dx.doi.org/10.1136/jitc-2022-004638 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Basic Tumor Immunology Brouwer, Thomas P de Vries, Natasja L Abdelaal, Tamim Krog, Ricki T Li, Zheng Ruano, Dina Fariña, Arantza Lelieveldt, Boudewijn P F Morreau, Hans Bonsing, Bert A Vahrmeijer, Alexander L Koning, Frits de Miranda, Noel F C C Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
title | Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
title_full | Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
title_fullStr | Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
title_full_unstemmed | Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
title_short | Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
title_sort | local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9260840/ https://www.ncbi.nlm.nih.gov/pubmed/35793870 http://dx.doi.org/10.1136/jitc-2022-004638 |
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