Title
Local and systemic immune profiles of human pancreatic ductal adenocarcinoma revealed by single-cell mass cytometry
Author
Brouwer, Thomas P. (Leiden University Medical Center)
de Vries, Natasja L. (Leiden University Medical Center)
Abdelaal, T.R.M. (TU Delft Pattern Recognition and Bioinformatics; Leiden University Medical Center) 
Li, Zheng (Leiden University Medical Center)
Ruano, Dina (Leiden University Medical Center)
Fariña, Arantza (Cancer Center Amsterdam)
Lelieveldt, B.P.F. (TU Delft Pattern Recognition and Bioinformatics; Leiden University Medical Center)
Morreau, Hans (Leiden University Medical Center)
Vahrmeijer, Alexander L. (Leiden University Medical Center)
Date
2022
Abstract
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.
Subject
gastrointestinal neoplasms
lymphocytes, tumor-infiltrating
tumor microenvironment
To reference this document use:
http://resolver.tudelft.nl/uuid:525ee67d-f913-4283-9714-91a233dd1ac8
DOI
https://doi.org/10.1136/jitc-2022-004638
Source
Journal for ImmunoTherapy of Cancer, 10 (7)
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2022 Thomas P. Brouwer, Natasja L. de Vries, T.R.M. Abdelaal, Zheng Li, Dina Ruano, Arantza Fariña, B.P.F. Lelieveldt, Hans Morreau, Alexander L. Vahrmeijer, More Authors