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Published in: Lung 1/2019

01-02-2019 | PLEURAL DISEASE

Cytotoxic Natural Killer Subpopulations as a Prognostic Factor of Malignant Pleural Effusion

Authors: Susana Herrera Lara, Estrella Fernández-Fabrellas, Gustavo Juan Samper, Josefa Marco Buades, Rafael Andreu Lapiedra, Amparo Pinilla Moreno, María Morales Suárez-Varela

Published in: Lung | Issue 1/2019

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Abstract

Background

Malignant pleural effusion (MPE) is a sign of advanced disease of poor prognosis. As natural killer (NK) cells are involved in the first line of tumour defence, we aimed to validate a new diagnostic and prognostic indicator for MPE based on NK subpopulations of pleural fluid (PF) and peripheral blood (PB).

Methods

NK subpopulations were determined in PF and PB in 71 patients with malignant, paramalignant or benign pleural effusion. The receiver operating characteristic (ROC) curves, Kaplan–Meier, multivariable Cox model and decision trees created with the CHAID (Chi-square automatic interaction detector) methodology were employed.

Results

We demonstrated that the PF/PB ratios of the CD56 bright CD16− and CD56 dim CD16− NK subpopulations were higher (p = 0.013 and p = 0.003, respectively) in MPEs and paramalignant pleural effusions (PPEs) than in benign ones, with an AUC of 0.757 and 0.741, respectively. The PF/PB ratio of CD16+ NK and CD57+ NK obtained a higher hazard ratio (HR) in the crude Cox’s regression analysis. In the adjusted Cox’s regression analysis, the PF/PB ratio of CD16+ NK gave the highest HR (HR 6.1 [1.76–21.1]) (p = 0.004). In the decision tree created for the MPE prognosis, we observed that the main predictor variable among the studied clinical, radiological, and analytical variables was lung mass, and that 92.9% of the patients who survived had a PF/PB ratio of the CD56 dim CD16+ NK subpopulation ≤ 0.43.

Conclusions

Our data suggest that both the PF/PB ratios of cytotoxic subpopulations CD57+ NK and CD16+ NK are useful as a prognostic factor of MPE. Other subpopulations (CD56 bright CD16− and CD56 dim CD16− NK) could help to diagnose MPE.
Literature
1.
go back to reference Villena Garrido V, Cases Viedma E, Fernández Villar A, de Pablo Gafas A, Pérez Rodríguez E, Porcel Pérez JM et al (2014) Normativa sobre el diagnóstico y tratamiento del derrame pleural. Actualización. Arch Bronconeumol 50:235–249CrossRefPubMed Villena Garrido V, Cases Viedma E, Fernández Villar A, de Pablo Gafas A, Pérez Rodríguez E, Porcel Pérez JM et al (2014) Normativa sobre el diagnóstico y tratamiento del derrame pleural. Actualización. Arch Bronconeumol 50:235–249CrossRefPubMed
2.
go back to reference Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ (2010) Management of a malignant pleural effusion: British Thoracic Society pleural disease guideline 2010. Thorax 65(Suppl 2):ii32–ii40CrossRef Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ (2010) Management of a malignant pleural effusion: British Thoracic Society pleural disease guideline 2010. Thorax 65(Suppl 2):ii32–ii40CrossRef
3.
go back to reference Cornfield DB, Gheith SM (2009) Flow cytometric quantitation of natural killer cells and T lymphocytes expressing T-cell receptors alpha/beta and gamma/delta is not helpful in distinguishing benign from malignant body cavity effusions. Cytom B 76:213–217CrossRef Cornfield DB, Gheith SM (2009) Flow cytometric quantitation of natural killer cells and T lymphocytes expressing T-cell receptors alpha/beta and gamma/delta is not helpful in distinguishing benign from malignant body cavity effusions. Cytom B 76:213–217CrossRef
4.
go back to reference Green LK, Griffin J (1996) Increased natural killer cells in fluids. A new, sensitive means of detecting carcinoma. Acta Cytol 40:1240–1245CrossRefPubMed Green LK, Griffin J (1996) Increased natural killer cells in fluids. A new, sensitive means of detecting carcinoma. Acta Cytol 40:1240–1245CrossRefPubMed
5.
go back to reference Yu GH, Hida CA, Salhany KE, Baloch Z, Gupta PK (1999) Immunohistochemical detection of cytotoxic lymphocytes in malignant serous effusions. Diagn Cytopathol 21:18–21CrossRefPubMed Yu GH, Hida CA, Salhany KE, Baloch Z, Gupta PK (1999) Immunohistochemical detection of cytotoxic lymphocytes in malignant serous effusions. Diagn Cytopathol 21:18–21CrossRefPubMed
6.
go back to reference Laurini JA, Garcia A, Elsner B, Bellotti M, Rescia C (2000) Relation between natural killer cells and neoplastic cells in serous fluids. Diagn Cytopathol 22:347–350CrossRefPubMed Laurini JA, Garcia A, Elsner B, Bellotti M, Rescia C (2000) Relation between natural killer cells and neoplastic cells in serous fluids. Diagn Cytopathol 22:347–350CrossRefPubMed
7.
go back to reference Sikora J, Dworacki G, Trybus M, Batura-Gabryel H, Zeromski J (1998) Correlation between DNA content, expression of Ki-67 antigen of tumor cells and immunophenotype of lymphocytes from malignant pleural effusions. Tumor Biol 19:196–204CrossRef Sikora J, Dworacki G, Trybus M, Batura-Gabryel H, Zeromski J (1998) Correlation between DNA content, expression of Ki-67 antigen of tumor cells and immunophenotype of lymphocytes from malignant pleural effusions. Tumor Biol 19:196–204CrossRef
8.
go back to reference Jezewska E, Sikora J, Slowik-Gabryelska A, Zeromski J (1993) Evaluation of immunophenotype of lymphoid cells isolated from malignant pleural effusions. Arch Immunol Ther Exp 41:51–56 Jezewska E, Sikora J, Slowik-Gabryelska A, Zeromski J (1993) Evaluation of immunophenotype of lymphoid cells isolated from malignant pleural effusions. Arch Immunol Ther Exp 41:51–56
9.
go back to reference Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J (2009) CD56 bright natural killer (NK) cells: an important NK cell subset. Immunology 126:458–465CrossRefPubMedPubMedCentral Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J (2009) CD56 bright natural killer (NK) cells: an important NK cell subset. Immunology 126:458–465CrossRefPubMedPubMedCentral
10.
go back to reference Focosi D, Bestagno M, Burrone O, Petrini MCD (2010) 57+ T lymphocytes and functional immune deficiency. J Leukoc Biol 87:107–116CrossRefPubMed Focosi D, Bestagno M, Burrone O, Petrini MCD (2010) 57+ T lymphocytes and functional immune deficiency. J Leukoc Biol 87:107–116CrossRefPubMed
11.
go back to reference Lopez-Vergès S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H et al (2010) CD57 defines a functionally distinct population of mature NK cells in the human CD56 dim CD16+ NK-cell subset. Blood 116:3865–3874CrossRefPubMedPubMedCentral Lopez-Vergès S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H et al (2010) CD57 defines a functionally distinct population of mature NK cells in the human CD56 dim CD16+ NK-cell subset. Blood 116:3865–3874CrossRefPubMedPubMedCentral
12.
go back to reference Nielsen CM, White MJ, Goodier MR, Riley EM (2013) Functional significance of CD57 expression on human NK cells and relevance to disease. Front Immunol 4:422CrossRefPubMedPubMedCentral Nielsen CM, White MJ, Goodier MR, Riley EM (2013) Functional significance of CD57 expression on human NK cells and relevance to disease. Front Immunol 4:422CrossRefPubMedPubMedCentral
13.
go back to reference Villena Garrido V, Ferrer Sancho J, Hernández Blasco L, de Pablo Gafas A, Pérez Rodríguez E, Rodríguez Panadero F et al (2006) Diagnóstico y tratamiento del derrame pleural. Arch Bronconeumol 42:349–372CrossRefPubMed Villena Garrido V, Ferrer Sancho J, Hernández Blasco L, de Pablo Gafas A, Pérez Rodríguez E, Rodríguez Panadero F et al (2006) Diagnóstico y tratamiento del derrame pleural. Arch Bronconeumol 42:349–372CrossRefPubMed
14.
go back to reference American Thoracic Society (2000) Management of malignant pleura effusions. Am J Respir Crit Care Med 162:1987–2001CrossRef American Thoracic Society (2000) Management of malignant pleura effusions. Am J Respir Crit Care Med 162:1987–2001CrossRef
15.
go back to reference Biggs D, De Ville B, Suen E (1991) A method of choosing multiway partitions for classification and decision trees. J Appl Stat 18:49–62CrossRef Biggs D, De Ville B, Suen E (1991) A method of choosing multiway partitions for classification and decision trees. J Appl Stat 18:49–62CrossRef
16.
go back to reference Scherpereel A, Grigoriu BD, Noppen M, Gey T, Chahine B, Baldacci S et al (2013) Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid. BMC Cancer 13:324CrossRefPubMedPubMedCentral Scherpereel A, Grigoriu BD, Noppen M, Gey T, Chahine B, Baldacci S et al (2013) Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid. BMC Cancer 13:324CrossRefPubMedPubMedCentral
17.
go back to reference Pace E, Di Sano C, Ferraro M, Tipa A, Olivieri D, Spatafora M et al (2011) Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions. Eur J Cancer 47:296–304CrossRefPubMed Pace E, Di Sano C, Ferraro M, Tipa A, Olivieri D, Spatafora M et al (2011) Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions. Eur J Cancer 47:296–304CrossRefPubMed
18.
go back to reference Atanackovic D, Block A, de Weerth A, Faltz C, Hossfeld DK, Hegewisch-Becker S (2004) Characterization of effusion-infiltrating T cells: benign versus malignant effusions. Clin Cancer Res 10:2600–2608CrossRefPubMed Atanackovic D, Block A, de Weerth A, Faltz C, Hossfeld DK, Hegewisch-Becker S (2004) Characterization of effusion-infiltrating T cells: benign versus malignant effusions. Clin Cancer Res 10:2600–2608CrossRefPubMed
19.
go back to reference Vacca P, Martini S, Garelli V, Passalacqua G, Moretta L, Mingari MC (2013) NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong anti-tumor activity on short-term IL-2 activation. Eur J Immunol 43:550–561CrossRefPubMed Vacca P, Martini S, Garelli V, Passalacqua G, Moretta L, Mingari MC (2013) NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong anti-tumor activity on short-term IL-2 activation. Eur J Immunol 43:550–561CrossRefPubMed
20.
go back to reference Qi J, Li D, Feng J, Yang S, Su Y, Fang M et al (2013) Native soluble carcinoembryonic antigen is not involved in the impaired activity of CD56 natural killer cells in malignant pleural effusion. Respiration 86:216–223CrossRefPubMed Qi J, Li D, Feng J, Yang S, Su Y, Fang M et al (2013) Native soluble carcinoembryonic antigen is not involved in the impaired activity of CD56 natural killer cells in malignant pleural effusion. Respiration 86:216–223CrossRefPubMed
21.
go back to reference Park BG, Park CJ, Yoon CH, Jang S, Chi HS, Ryu MH et al (2013) The extended leukocyte differential count using the Cytodiff flow cytometric system reveals that higher CD16+ cytotoxic NK+ T lymphocyte levels predict superior survival outcomes in patients with metastatic carcinoma. Cytom B 84:202–204CrossRef Park BG, Park CJ, Yoon CH, Jang S, Chi HS, Ryu MH et al (2013) The extended leukocyte differential count using the Cytodiff flow cytometric system reveals that higher CD16+ cytotoxic NK+ T lymphocyte levels predict superior survival outcomes in patients with metastatic carcinoma. Cytom B 84:202–204CrossRef
22.
go back to reference Sconocchia G, Zlobec I, Lugli A, Calabrese D, Iezzi G, Karamitopoulou E et al (2011) Tumor infiltration by FcγRIII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma. Int J Cancer 128:2663–2672CrossRefPubMed Sconocchia G, Zlobec I, Lugli A, Calabrese D, Iezzi G, Karamitopoulou E et al (2011) Tumor infiltration by FcγRIII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma. Int J Cancer 128:2663–2672CrossRefPubMed
23.
go back to reference Dong HP, Elstrand MB, Holth A, Silins I, Berner A, Trope CG et al (2006) NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am J Clin Pathol 125:451–458CrossRefPubMed Dong HP, Elstrand MB, Holth A, Silins I, Berner A, Trope CG et al (2006) NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am J Clin Pathol 125:451–458CrossRefPubMed
Metadata
Title
Cytotoxic Natural Killer Subpopulations as a Prognostic Factor of Malignant Pleural Effusion
Authors
Susana Herrera Lara
Estrella Fernández-Fabrellas
Gustavo Juan Samper
Josefa Marco Buades
Rafael Andreu Lapiedra
Amparo Pinilla Moreno
María Morales Suárez-Varela
Publication date
01-02-2019
Publisher
Springer US
Published in
Lung / Issue 1/2019
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
DOI
https://doi.org/10.1007/s00408-018-0186-7

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