Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry.

Autor:	Brouwer TP; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., de Vries NL; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands., Abdelaal T; Pattern recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands.; Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands., Krog RT; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Li Z; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Ruano D; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Fariña A; Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands., Lelieveldt BPF; Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands.; Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands., Morreau H; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands., Bonsing BA; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., Vahrmeijer AL; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands., Koning F; Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands., de Miranda NFCC; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands N.F.de_Miranda@lumc.nl.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jul; Vol. 10 (7).
DOI:	10.1136/jitc-2022-004638
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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