NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong antitumor activity on short-term IL-2 activation

Our plain-English summary of NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong antitumor activity on short-term IL-2 activation, by P. Vacca, S. Martini, V. Garelli, et al (European Journal of Immunology, 2013).

The study

• Authors: P. Vacca, S. Martini, V. Garelli, G. Passalacqua, L. Moretta, M.C. Mingari
• Journal: European Journal of Immunology
• Published: 2013;43(2):550-61
• Cited by: 39 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

NK cells are a major component of innate immunity and exert a potent antitumor effect both in vitro and in vivo. However, NK cells infiltrating solid tumors have been shown to display severely impaired functional capabilities. In this study, we analyzed NK cells present in pleural effusions (PEs) of patients with primary or metastatic tumors of different origin, including mesothelioma and lung, breast, colon, gastric, bladder, and uterus carcinoma. In all instances, freshly isolated PE-NK cells displayed a CD56(bright) phenotype and expressed normal levels of both activating receptors and HLA class I-specific inhibitory receptors. In addition, they rapidly released large amounts of IFN-γ and TNF-α after stimulation. Upon culture in IL-2, they acquired a potent cytolytic activity against both allogeneic and autologous tumor cells. Tumor cell lysis was primarily mediated by NKG2D and NKp30 and partially by NKp46 and DNAM-1, in agreement with the expression of the corresponding ligands on tumor cells. The finding that PE-NK cells are not functionally impaired and that they can efficiently kill tumor cells upon short-term IL-2 activation may offer important clues for the development of novel approaches in tumor immunotherapy.

© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In plain English

This laboratory study from Genova, Italy, examined natural killer (NK) cells, a type of immune cell. They were taken from the fluid around the lungs (pleural effusion) and from the blood of 25 cancer patients. Twelve had mesothelioma of the pleura. The others had cancers that began in the lung, colon, stomach, breast, bladder or uterus. The article does not discuss asbestos. Freshly collected NK cells from the pleural fluid were mostly of the type called CD56bright. Most of their activating receptors were at levels comparable to blood NK cells. After stimulation they released the signaling proteins IFN-γ and TNF-α. After three days in the growth factor IL-2 they carried more activating receptors and killing proteins. The killing tests used cells grown in IL-2 for 2 to 4 weeks. In these tests, the fluid NK cells killed laboratory tumor cells, including the patient's own tumor cells, more efficiently than that patient's blood NK cells. The authors concluded that these NK cells were not functionally impaired. They suggested that giving IL-2 locally might boost this activity in patients, which this study did not test.

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 immune cells collected from patients (cell analysis and cell-killing experiments in the laboratory)
• Who was studied: 25 patients with primary or metastatic tumors, aged 49 to 96, 22 men and 3 women, Genova, Italy. Blood and pleural effusion were collected from each patient at the same time. According to Table 1, 12 had mesothelioma originating in the pleura, 6 had lung tumors, 3 colon, and 1 each gastric, breast, bladder and uterus. Study dates are not given. Blood from a healthy donor was used as a control.
• Exposure: No asbestos or other environmental exposure was studied, and the article does not mention asbestos. In the laboratory, cells were cultured with IL-2: 100 U/mL for 3 days (short-term), or expanded for 2 to 4 weeks (long-term).
• Main results:
  • Fresh NK cells from pleural effusion were highly enriched in CD56bright CD16low cells. Blood NK cells were mostly CD56dim CD16+.
  • In fresh pleural effusion NK cells, the activating receptors NKp30, NKG2D, DNAM-1 and 2B4 were at levels comparable to the same patients' blood NK cells.
  • After stimulation, fresh pleural effusion NK cells produced IFN-γ and TNF-α at levels even higher than the same patients' resting blood NK cells.
  • After 72 hours in IL-2, pleural effusion NK cells showed increased expression of the activating receptors NKp30, NKp44, NKG2D and DNAM-1, compared with fresh pleural effusion NK cells.
  • Long-term IL-2-activated NK cells from patient #5 were shown as one representative experiment out of four. Pleural effusion NK cells reached 60% lysis of the patient's own tumor cells at an effector-to-target ratio printed as 0,6:1, versus 2,5:1 for that patient's blood NK cells.
  • Blocking the receptors NKG2D or NKp30 inhibited tumor cell killing. Blocking NKp46, NKp44 or DNAM-1 reduced killing only partially.
• The authors' conclusion: The authors concluded that NK cells in pleural effusions from cancer patients are not anergic (functionally switched off). They suggested that local IL-2 infusion might induce or boost their antitumor activity in patients.
• Limitations the authors state:
  • Because too few short-term IL-2-activated NK cells were available, the tumor-killing experiments used NK cells expanded in IL-2 for 2 to 4 weeks.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Cytokine, Mesothelioma, Carcinoma, Immunotherapy.

Related studies

• Asbestos and cancer: human natural killer cell activity is suppressed by asbestos fibers but can be restored by recombinant interleukin-2 — B.W. Robinson (1989)
• Longitudinal Measurement of Pleural Fluid Biochemistry and Cytokines in Malignant Pleural Effusions — R. Thomas, H.M. Cheah, et al. (2016)
• IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase — C. Jackaman, S. Lansley, et al. (2012)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• Decrease in phosphorylation of ERK following decreased expression of NK cell-activating receptors in human NK cell line exposed to asbestos — Y. Nishimura, M. Maeda, et al. (2009)
• Natural killer cell activity in asbestos workers. Interactive effects of smoking and asbestos exposure — R.D. deShazo, J. Morgan, et al. (1988)

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