Skip to main content
Top
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Lymphoma | Research article

Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients

Authors: R-M Amini, G. Enblad, P. Hollander, S. Laszlo, E. Eriksson, K. Ayoola Gustafsson, A. Loskog, I. Thörn

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome.

Methods

Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome.

Results

The percentage of CD3-positive T-cells was lower (p = 0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p = 0.2) nor the T-cell/monocyte ratio (p = 0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7+/CD3/CD56bright/CD16dim/−) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p = 0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p = 0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p = 0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p = 0.04).

Conclusions

An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.
Appendix
Available only for authorised users
Literature
1.
go back to reference Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International prognostic factors project on advanced Hodgkin's disease. N Engl J Med. 1998;339(21):1506–14. Epub 1998/11/20.CrossRef Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International prognostic factors project on advanced Hodgkin's disease. N Engl J Med. 1998;339(21):1506–14. Epub 1998/11/20.CrossRef
2.
go back to reference Barath S, Aleksza M, Keresztes K, Toth J, Sipka S, Szegedi G, et al. Immunoregulatory T cells in the peripheral blood of patients with Hodgkin's lymphoma. Acta Haematol. 2006;116(3):181–5 Epub 2006/10/04.CrossRef Barath S, Aleksza M, Keresztes K, Toth J, Sipka S, Szegedi G, et al. Immunoregulatory T cells in the peripheral blood of patients with Hodgkin's lymphoma. Acta Haematol. 2006;116(3):181–5 Epub 2006/10/04.CrossRef
3.
go back to reference Vassilakopoulos TP, Dimopoulou MN, Angelopoulou MK, Petevi K, Pangalis GA, Moschogiannis M, et al. Prognostic implication of the absolute lymphocyte to absolute monocyte count ratio in patients with classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and Dacarbazine or equivalent regimens. Oncologist. 2016;21(3):343–53. Epub 2016/02/28.CrossRef Vassilakopoulos TP, Dimopoulou MN, Angelopoulou MK, Petevi K, Pangalis GA, Moschogiannis M, et al. Prognostic implication of the absolute lymphocyte to absolute monocyte count ratio in patients with classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and Dacarbazine or equivalent regimens. Oncologist. 2016;21(3):343–53. Epub 2016/02/28.CrossRef
4.
go back to reference Tadmor T, Bari A, Marcheselli L, Sacchi S, Aviv A, Baldini L, et al. Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: evaluation based on data from 1450 patients. Mayo Clin Proc. 2015;90(6):756–64. Epub 2015/06/06.CrossRef Tadmor T, Bari A, Marcheselli L, Sacchi S, Aviv A, Baldini L, et al. Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: evaluation based on data from 1450 patients. Mayo Clin Proc. 2015;90(6):756–64. Epub 2015/06/06.CrossRef
5.
go back to reference Lin B, Chen C, Qian Y, Feng J. Prognostic role of peripheral blood lymphocyte/monocyte ratio at diagnosis in diffuse large B-cell lymphoma: a meta-analysis. Leuk Lymphoma. 2015;56(9):2563–8. Epub 2015/02/18.CrossRef Lin B, Chen C, Qian Y, Feng J. Prognostic role of peripheral blood lymphocyte/monocyte ratio at diagnosis in diffuse large B-cell lymphoma: a meta-analysis. Leuk Lymphoma. 2015;56(9):2563–8. Epub 2015/02/18.CrossRef
6.
go back to reference Belotti A, Doni E, Bolis S, Rossini F, Casaroli I, Pezzatti S, et al. Peripheral blood lymphocyte/monocyte ratio predicts outcome in follicular lymphoma and in diffuse large B-cell lymphoma patients in the rituximab era. Clin Lymphoma, Myeloma Leuk. 2015;15(4):208–13. Epub 2014/12/04.CrossRef Belotti A, Doni E, Bolis S, Rossini F, Casaroli I, Pezzatti S, et al. Peripheral blood lymphocyte/monocyte ratio predicts outcome in follicular lymphoma and in diffuse large B-cell lymphoma patients in the rituximab era. Clin Lymphoma, Myeloma Leuk. 2015;15(4):208–13. Epub 2014/12/04.CrossRef
7.
go back to reference Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res. 2010;107:57–117 Epub 2010/04/20.CrossRef Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res. 2010;107:57–117 Epub 2010/04/20.CrossRef
8.
go back to reference Hus I, Bojarska-Junak A, Kaminska M, Dobrzynska-Rutkowska A, Szatan K, Szymczyk A, et al. Imbalance in circulatory iNKT, Th17 and T regulatory cell frequencies in patients with B-cell non-Hodgkin's lymphoma. Oncol Lett. 2017;14(6):7957–64. Epub 2017/12/19.PubMedPubMedCentral Hus I, Bojarska-Junak A, Kaminska M, Dobrzynska-Rutkowska A, Szatan K, Szymczyk A, et al. Imbalance in circulatory iNKT, Th17 and T regulatory cell frequencies in patients with B-cell non-Hodgkin's lymphoma. Oncol Lett. 2017;14(6):7957–64. Epub 2017/12/19.PubMedPubMedCentral
9.
go back to reference Gunduz E, Sermet S, Musmul A. Peripheral blood regulatory T cell levels are correlated with some poor prognostic markers in newly diagnosed lymphoma patients. Cytometry B Clin Cytom. 2016;90(5):449–54 Epub 2015/10/08.CrossRef Gunduz E, Sermet S, Musmul A. Peripheral blood regulatory T cell levels are correlated with some poor prognostic markers in newly diagnosed lymphoma patients. Cytometry B Clin Cytom. 2016;90(5):449–54 Epub 2015/10/08.CrossRef
10.
go back to reference Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792 Epub 2015/06/19.CrossRef Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792 Epub 2015/06/19.CrossRef
11.
go back to reference Vari F, Arpon D, Keane C, Hertzberg MS, Talaulikar D, Jain S, et al. Immune evasion via PD-1/PD-L1 on NK-cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood. 2018;131(16):1809–19 Epub 2018/02/17. Vari F, Arpon D, Keane C, Hertzberg MS, Talaulikar D, Jain S, et al. Immune evasion via PD-1/PD-L1 on NK-cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood. 2018;131(16):1809–19 Epub 2018/02/17.
12.
go back to reference Parham P. Taking license with natural killer cell maturation and repertoire development. Immunol Rev. 2006;214:155–60 Epub 2006/11/15.CrossRef Parham P. Taking license with natural killer cell maturation and repertoire development. Immunol Rev. 2006;214:155–60 Epub 2006/11/15.CrossRef
13.
go back to reference Michel T, Poli A, Cuapio A, Briquemont B, Iserentant G, Ollert M, et al. Human CD56bright NK cells: an update. J Immunol. 2016;196(7):2923–31 Epub 2016/03/20.CrossRef Michel T, Poli A, Cuapio A, Briquemont B, Iserentant G, Ollert M, et al. Human CD56bright NK cells: an update. J Immunol. 2016;196(7):2923–31 Epub 2016/03/20.CrossRef
14.
go back to reference Kloss S, Chambron N, Gardlowski T, Arseniev L, Koch J, Esser R, et al. Increased sMICA and TGFbeta1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells. Oncoimmunology. 2015;4(11):e1055993 Epub 2015/10/10.CrossRef Kloss S, Chambron N, Gardlowski T, Arseniev L, Koch J, Esser R, et al. Increased sMICA and TGFbeta1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells. Oncoimmunology. 2015;4(11):e1055993 Epub 2015/10/10.CrossRef
15.
go back to reference Mamessier E, Pradel LC, Thibult ML, Drevet C, Zouine A, Jacquemier J, et al. Peripheral blood NK cells from breast cancer patients are tumor-induced composite subsets. J Immunol. 2013;190(5):2424–36 Epub 2013/01/30.CrossRef Mamessier E, Pradel LC, Thibult ML, Drevet C, Zouine A, Jacquemier J, et al. Peripheral blood NK cells from breast cancer patients are tumor-induced composite subsets. J Immunol. 2013;190(5):2424–36 Epub 2013/01/30.CrossRef
16.
go back to reference Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74. Epub 2009/02/07.CrossRef Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74. Epub 2009/02/07.CrossRef
17.
go back to reference Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150. Epub 2016/07/07.CrossRef Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150. Epub 2016/07/07.CrossRef
18.
go back to reference Betsch A, Rutgeerts O, Fevery S, Sprangers B, Verhoef G, Dierickx D, et al. Myeloid-derived suppressor cells in lymphoma: the good, the bad and the ugly. Blood Rev. 2018; Epub 2018/04/25. Betsch A, Rutgeerts O, Fevery S, Sprangers B, Verhoef G, Dierickx D, et al. Myeloid-derived suppressor cells in lymphoma: the good, the bad and the ugly. Blood Rev. 2018; Epub 2018/04/25.
19.
go back to reference Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med. 2016;14(1):282 Epub 2016/10/01.CrossRef Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med. 2016;14(1):282 Epub 2016/10/01.CrossRef
20.
go back to reference Manson G, Houot R. Next generation immunotherapies for lymphoma: one foot in the future. Ann Oncol. 2018;29(3):588–601 Epub 2018/01/25. Manson G, Houot R. Next generation immunotherapies for lymphoma: one foot in the future. Ann Oncol. 2018;29(3):588–601 Epub 2018/01/25.
21.
go back to reference Glimelius B, Melin B, Enblad G, Alafuzoff I, Beskow A, Ahlstrom H, et al. U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden. Acta Oncol. 2018;57(2):187–94 Epub 2017/06/21.CrossRef Glimelius B, Melin B, Enblad G, Alafuzoff I, Beskow A, Ahlstrom H, et al. U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden. Acta Oncol. 2018;57(2):187–94 Epub 2017/06/21.CrossRef
22.
go back to reference Swerdlow SH CE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues: WHO/IARC; 2016. Swerdlow SH CE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues: WHO/IARC; 2016.
23.
go back to reference Tullgren O, Grimfors G, Holm G, Johansson B, Svedmyr E, Wedelin C, et al. Lymphocyte abnormalities predicting a poor prognosis in Hodgkin's disease. A long-term follow-up. Cancer. 1991;68(4):768–75 Epub 1991/08/15.CrossRef Tullgren O, Grimfors G, Holm G, Johansson B, Svedmyr E, Wedelin C, et al. Lymphocyte abnormalities predicting a poor prognosis in Hodgkin's disease. A long-term follow-up. Cancer. 1991;68(4):768–75 Epub 1991/08/15.CrossRef
24.
go back to reference Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA. Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing. 2006;3:10 Epub 2006/12/01.CrossRef Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA. Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun Ageing. 2006;3:10 Epub 2006/12/01.CrossRef
25.
go back to reference Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG, et al. Immunosenescence of human natural killer cells. J Innate Immun. 2011;3(4):337–43 Epub 2011/05/18.CrossRef Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG, et al. Immunosenescence of human natural killer cells. J Innate Immun. 2011;3(4):337–43 Epub 2011/05/18.CrossRef
26.
go back to reference Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65 Epub 2014/06/27.CrossRef Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65 Epub 2014/06/27.CrossRef
27.
go back to reference Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C, et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol, Immunother. 2016;65(2):161–9. Epub 2016/01/06.CrossRef Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C, et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol, Immunother. 2016;65(2):161–9. Epub 2016/01/06.CrossRef
28.
go back to reference Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V, et al. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry B Clin Cytom. 2015;88(2):77–91. Epub 2014/12/17.CrossRef Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V, et al. Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry B Clin Cytom. 2015;88(2):77–91. Epub 2014/12/17.CrossRef
29.
go back to reference Gorczyca W. Flow cytometry in neoplastic hematology morphologic-Immunophenotypic correlation: Informa Health Care; 2017. Gorczyca W. Flow cytometry in neoplastic hematology morphologic-Immunophenotypic correlation: Informa Health Care; 2017.
30.
go back to reference Zhou L, Somasundaram R, Nederhof RF, Dijkstra G, Faber KN, Peppelenbosch MP, et al. Impact of human granulocyte and monocyte isolation procedures on functional studies. Clin Vaccine Immunol. 2012;19(7):1065–74. Epub 2012/05/04.CrossRef Zhou L, Somasundaram R, Nederhof RF, Dijkstra G, Faber KN, Peppelenbosch MP, et al. Impact of human granulocyte and monocyte isolation procedures on functional studies. Clin Vaccine Immunol. 2012;19(7):1065–74. Epub 2012/05/04.CrossRef
31.
go back to reference Roussel M, Irish JM, Menard C, Lhomme F, Tarte K, Fest T. Regulatory myeloid cells: an underexplored continent in B-cell lymphomas. Cancer Immunol, Immunother. 2017;66(8):1103–11. Epub 2017/07/10.CrossRef Roussel M, Irish JM, Menard C, Lhomme F, Tarte K, Fest T. Regulatory myeloid cells: an underexplored continent in B-cell lymphomas. Cancer Immunol, Immunother. 2017;66(8):1103–11. Epub 2017/07/10.CrossRef
32.
go back to reference Shoji H, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, et al. The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy. Oncotarget. 2017;8(56):95083–94 Epub 2017/12/10.CrossRef Shoji H, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, et al. The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy. Oncotarget. 2017;8(56):95083–94 Epub 2017/12/10.CrossRef
33.
go back to reference Gonda K, Shibata M, Ohtake T, Matsumoto Y, Tachibana K, Abe N, et al. Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer. Oncol Lett. 2017;14(2):1766–74. Epub 2017/08/10.CrossRef Gonda K, Shibata M, Ohtake T, Matsumoto Y, Tachibana K, Abe N, et al. Myeloid-derived suppressor cells are increased and correlated with type 2 immune responses, malnutrition, inflammation, and poor prognosis in patients with breast cancer. Oncol Lett. 2017;14(2):1766–74. Epub 2017/08/10.CrossRef
34.
go back to reference Marini O, Spina C, Mimiola E, Cassaro A, Malerba G, Todeschini G, et al. Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients. Oncotarget. 2016;7(19):27676–88. Epub 2016/04/07.CrossRef Marini O, Spina C, Mimiola E, Cassaro A, Malerba G, Todeschini G, et al. Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients. Oncotarget. 2016;7(19):27676–88. Epub 2016/04/07.CrossRef
35.
go back to reference Abdulla M, Laszlo S, Triumf J, Hedstrom G, Berglund M, Enblad G, et al. A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients. Acta Oncol. 2016;55(9–10):1126–31. Epub 2016/08/24.CrossRef Abdulla M, Laszlo S, Triumf J, Hedstrom G, Berglund M, Enblad G, et al. A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients. Acta Oncol. 2016;55(9–10):1126–31. Epub 2016/08/24.CrossRef
36.
go back to reference Hollander P, Rostgaard K, Smedby KE, Molin D, Loskog A, de Nully Brown P, et al. An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome. Eur J Haematol. 2018;100(1):88–97. Epub 2017/10/25.CrossRef Hollander P, Rostgaard K, Smedby KE, Molin D, Loskog A, de Nully Brown P, et al. An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome. Eur J Haematol. 2018;100(1):88–97. Epub 2017/10/25.CrossRef
Metadata
Title
Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients
Authors
R-M Amini
G. Enblad
P. Hollander
S. Laszlo
E. Eriksson
K. Ayoola Gustafsson
A. Loskog
I. Thörn
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5529-0

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine