Presence of innate lymphoid cells in pleural effusions of primary and metastatic tumors: Functional analysis and expression of PD-1 receptor

Our plain-English summary of Presence of innate lymphoid cells in pleural effusions of primary and metastatic tumors: Functional analysis and expression of PD-1 receptor, by N. Tumino, S. Martini, E. Munari, et al (International Journal of Cancer, 2019).

The study

• Authors: N. Tumino, S. Martini, E. Munari, F. Scordamaglia, F. Besi, F.R. Mariotti, G. Bogina, M.C. Mingari, P. Vacca, L. Moretta
• Journal: International Journal of Cancer
• Published: 2019;145(6):1660-1668
• Cited by: 76 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The tumor microenvironment (TM) contains a wide variety of cell types and soluble factors capable of suppressing immune responses. While the presence of NK cells in pleural effusions (PE) has been documented, no information exists on the presence of other innate lymphoid cell (ILC) subsets and on the expression of programmed cell death-1 (PD-1) in NK and ILC. The presence of ILC was assessed in PE of 54 patients (n = 33 with mesothelioma, n = 15 with adenocarcinoma and n = 6 with inflammatory pleural diseases) by cell staining with suitable antibody combinations and cytofluorimetric analysis. The cytokine production of ILC isolated from both PE and autologous peripheral blood was analyzed upon cell stimulation and intracytoplasmic staining. We show that, in addition to NK cells, also ILC1, ILC2 and ILC3 are present in malignant PE and that the prevalent subset is ILC3. PE-ILC subsets produced their typical sets of cytokines upon activation. In addition, we analyzed the PD-1 expression on NK/ILC by multiparametric flow-cytometric analysis, while the expression of PD-1 ligand (PD-L1) was evaluated by immunohistochemical analysis. Both NK cells and ILC3 expressed functional PD-1, moreover, both tumor samples and malignant PE-derived tumor cell lines were PD-L1+ suggesting that the interaction between PD-1+ ILC and PD-L1+ tumor cells may hamper antitumor immune responses mediated by NK and ILC.

© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

In plain English

This laboratory study, from Italy, examined immune cells in fluid drained from around the lungs (pleural effusions) of 54 patients: 33 with mesothelioma, 15 with cancers that had spread from elsewhere (mostly adenocarcinomas), and 6 with inflammatory pleural disease. The study did not look at asbestos exposure. Using flow cytometry, the authors found that, besides NK cells, the cancer-related fluids contained three other groups of innate lymphoid cells (ILC1, ILC2 and ILC3). ILC3 were the most common, at 72% of these helper cells, compared with 86% in the inflammatory fluids. Patterns were broadly similar in mesothelioma and adenocarcinoma fluids. When stimulated in the laboratory, the cells released their typical cytokines (immune signalling molecules). NK cells and ILC3 from the cancer-related fluids carried a receptor called PD-1, which was seen at very low levels on blood NK cells. Engaging PD-1 with an antibody significantly reduced cytokine release. Tumor cells expressed PD-1's partner molecule, PD-L1. The authors concluded that this interaction may hamper the immune cells' anti-tumor responses. They said the cells' role in tumor growth needs further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of cells from patient pleural effusion samples, using flow cytometry, cytokine stimulation tests and PD-L1 immunocytochemistry
• Who was studied: Pleural effusions from 54 patients in Italy. 33 had mesothelioma (12 listed as epithelioid mesothelioma, 21 as mesothelioma). 15 had metastatic tumors: 7 lung adenocarcinoma, 3 intestinal adenocarcinoma, 2 uterine carcinoma, and 1 each of breast carcinoma, pancreatic adenocarcinoma and bladder carcinoma. 6 had inflammatory pleural disease. Peripheral blood from healthy donors served as controls. Collection dates are not given.
• Main results:
  • Among helper innate lymphoid cells, the proportions of ILC1, ILC2 and ILC3 were 14%, 14% and 72% in malignant effusions. In inflammatory effusions they were 5%, 9% and 86%.
  • ILC3 were the most common subset in both mesothelioma and adenocarcinoma effusions. ILC1 and ILC2 were 12.1% and 16.9% in mesothelioma and 15.6% and 11.6% in adenocarcinoma.
  • When stimulated, the cells from malignant effusions produced their typical cytokines. ILC2 from the effusions produced much more IL-4 than ILC2 from the same patients' blood.
  • NK cells and ILC3 from malignant effusions expressed PD-1 in variable proportions (effusion samples n = 12). NK cells from the same patients' blood (n = 5) and from healthy donors' blood (n = 6) expressed very low levels.
  • Cytokine production triggered through activating receptors on NK cells and NCR+ ILC3 was significantly inhibited when an anti-PD-1 antibody was added (n = 7). Recombinant PD-L1 also reduced TNF-alpha and IFN-gamma production by NK cells.
  • PD-L1 was seen on tumor cells in adenocarcinoma effusion specimens. The authors reported PD-L1 on all cell lines grown from mesothelioma or adenocarcinoma effusions, but did not show these data. PD-L1 staining was performed on 40 samples (10 mesothelioma, 30 adenocarcinoma); results per sample are not given.
• The authors' conclusion: The authors concluded that interaction between PD-1 on NK cells and ILC and PD-L1 on tumor cells may hamper anti-tumor immune responses mediated by NK cells and ILC.
• Limitations the authors state:
  • The authors stated that how these cells interact with tumor cells, and whether they influence tumor progression or anti-tumor defenses, requires further investigation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Tumor Microenvironment, Mesothelioma, Adenocarcinoma, Cytokine, PD-L1.

Related studies

• The PD-L1/PD-1 pathway promotes dysfunction, but not "exhaustion", in tumor-responding T cells from pleural effusions in lung cancer patients — H. Prado-Garcia, S. Romero-Garcia, et al. (2017)
• Primary lesions that may imitate metastatic tumors histologically: A selective review — M.R. Wick (2018)
• Electron microscopy in the cytological examination of metastatic pleural effusions — M. Legrand, R. Pariente (1976)
• "Cannonballs" and psammoma bodies: unusual cytologic features of metastatic pulmonary small-cell carcinoma in a pleural effusion — A.B. Conway, M.K. Hart, et al. (2013)
• The value of anti-calretinin antibody in the differential diagnosis of normal and reactive mesothelia versus metastatic tumors in effusion cytology — H. Nagel, B. Hemmerlein, et al. (1998)
• Cytomorphological features of metastatic squamous cell carcinoma in serous effusions — C.C. Huang, C.W. Michael (2014)

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