Expression features of antigens involved in the formation of immunological synapse in splenic marginal zone lymphoma

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Abstract

Background. Splenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin’s B-cell lymphoma. It presents morphologically by mature lymphoid B-cells. They conform to these immunological characteristics of marginal zone lymphocytes from secondary follicles. The tumor B-cells of SMZL do not have specific markers of immunophenotype and requires the exclusion of other non-Hodgkin’s B-cell lymphomas. There is an annual increase in the incidence of SMZL. There are refractory forms and progressive course of the SMZL. There is a huge variety of the mechanisms of evading tumor cells from immunological control. Unlike solid tumors, B-lymphoproliferative diseases are characterized by the expression of HLA I/II and co-stimulatory molecules (CD80 and CD86). Therefore, tumor B-lymphocytes can act as antigen-presenting cells (APC) for T lymphocytes. The T-cell immune response is known to play an important role in antitumor control. It is known that effective activation of T-lymphocytes requires the formation of an immunological synapse and the presence of two activation signals (antigen recognition and co-stimulation of CD28-CD80/86). According to the modern concept of tumor development, there is a gradual selection of tumor clones. As a result, only tumor cells that are invisible to the immune system remain. Mechanisms of evasion of tumor B-cells of SMZL from immune surveillance are currently not fully understood and are being actively studied.

Objective: to study the expression features of antigens involved in the formation of immunological synapse in patients with SMZL in peripheral blood.

Materials and methods. The study includes 10 primary SMZL patients; all patients have stage IV according to the Ann Arbor classification. Splenectomy was performed for all patients as a first stage of treatment. Two patients had progression of SMZL after splenectomy, which required chemotherapy. The control group included 25 healthy donors. Peripheral blood was used as a material for analysis. The study was conducted on a 6-color BD FACS Canto II flow cytometer (BD Biosciences, USA) immediately after diagnosis.

Results. Tumor B-cells of SMZL are different from B-cells of healthy donors with a greater proportion of CD80+, FAS+, PD-1+-cells, which may correspond to activated B-cells. The proportion of CD4+PD-1+ and CD8+PD-1+ T-cells in patients with SMZL was higher in comparison with the control group. There was a large proportion of T-cells expressing PD-1 in the group of patients with SMZL progression after splenectomy in comparison with the group of patients with indolent course of SMZL. Conclusion. Thereby, tumor B-cells of the SMZL retains the features of non-tumor analogues. The most significant mechanism for evading immune surveillance in an SMZL is inhibition of the T-cell immunity via the PD-1–PD-L1 pathway. The most pronounced inhibition of T-cell immunity causes an uncontrolled tumor process.

About the authors

D. S. Badmazhapova

National Medical Research Center for Hematology, Ministry of Health of Russia

Author for correspondence.
Email: badmazhapova-darima@mail.ru
ORCID iD: 0000-0002-4223-2366

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

I. V. Galtseva

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-8490-6066

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

E. E. Zvonkov

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-2639-7419

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

Yu. O. Davydova

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0001-5932-0285

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

M. M. Kapranov

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-6512-910X

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

T. N. Moiseeva

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0001-9591-8508

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

A. M. Kovrigina

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0002-1082-8659

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

U. L. Julhakyan

National Medical Research Center for Hematology, Ministry of Health of Russia

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

K. I. Danishyan

National Medical Research Center for Hematology, Ministry of Health of Russia

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

K. R. Sabirov

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0003-3677-0480

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

E. N. Parovichnikova

National Medical Research Center for Hematology, Ministry of Health of Russia

ORCID iD: 0000-0001-6177-3566

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

V. G. Savchenko

National Medical Research Center for Hematology, Ministry of Health of Russia

4 Novyy Zykovskiy Proezd, Moscow 125167

Russian Federation

References

  1. Swerdlow S.H., Campo E., Harris N.L. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2017. Pp. 291–297.
  2. Julhakyan U.L., Grinshpun L.D. Splenic lymphoma form marginal zone cells (spleen lymphocytoma) in elderly patients: clinical features, diagnosis, treatment. In: Geriatric hematology. Blood diseases in the elderly patients. Eds.: L.D. Grinshpun, A.V. Pivnik. Moscow, 2012. Pp. 237–44. (In Russ.).
  3. Silaev M.A., Karagyulyan S.R., Bulanov A.Yu. et al. Splenectomy in massive and giant splenomegaly. Gematologiya i transfuziologiya = Hematology and Transfusiology 2011;56(1):6–10.(In Russ.)
  4. Julhakyan U.L., Obukhova T.N., Kaplanskaya I.B. Splenic marginal zone lymphocytoma with rearrangement of BCL6/3q27 gene. Gematologiya i transfuziologiya = Hematology and Transfusiology 2009;54(3):48–52. (In Russ.).
  5. Julhakyan U.L. Viral hepatitis and splenic marginal zone lymphoma: approaches to treatment. Klinicheskaya oncogematologia. Fundamental’nye issledovaniya i klinicheskaya praktika = Clinical Hematology Oncology. Basic Research and Clinical Practice 2012;6(1):120–3. (In Russ.).
  6. Julakyan U.L., Biderman B.V., Gemdzhian E.G. et al. Molecular analysis of immunoglobulin genes in the tumor B cells in splenic marginal zone lymphoma. Terapevticheskiy arkhiv = Therapeutic Archive 2015;87(7):58–63.(In Russ).
  7. Dunn G.P., Bruce A.T., Ikeda H. et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3(11):991–8. doi: 10.1038/ni1102-991.
  8. Vladimirova R., Popova D., Vikentieva E. et al. Chronic lymphocytic leukemia – microenvironment and B cells. Leuk Updat New Insights 2015. doi: 10.5772/60761.
  9. Yakutik I.A., Al’-Radi L.S., Julhakyan U.L. et al. BRAF and MAP2K1 mutations in hairy cell leukemia and splenic marginal zone B-cell lymphoma. Oncohematology 2016;11(1):34–6.(In Russ). doi: 10.17650/1818-8346-2016-11-1-34-36.
  10. Hanahan D., Weinberg R.A. The hallmarks of cancer. Cell Press 2000;100:57–70. doi: 10.1007/BF03091804.
  11. Dakappagari N., Ho S.N., Gascoyne R.D. et al. CD80 (B7.1) is expressed on both malignant B cells and nonmalignant stromal cells in non-Hodgkin lymphoma. Cytom Part B Clin Cytom 2012;82(2): 112–9. doi: 10.1002/cyto.b.20631.
  12. Chaperot L., Plumas J., Jacob M.C. et al. Functional expression of CD80 and CD86 allows immunogenicity of malignant B cells from non-Hodgkin’s lymphomas. Exp Hematol 1999;27(3):479–88. doi: 10.1016/S0301-472X(98)00059-9.
  13. Bogolyubova A.V., Efimov G.A., Drutskaya M.S. et al. Cancer immunotherapy based on the blockade of immune checkpoints. Med Immunol 2015;17(5):395. doi: 10.15789/15630625-2015-5-395-406.
  14. Janeway C.A., Travers P., Walport M. et al. Immunobiology: the immune system in health and disease. Immuno Biol 2001;(5):892. doi: 10.1111/j.1467-2494.1995.tb00120.x.
  15. Yarilin A.A. Fundamentals of IMmunology. Moscow: GEOTAR-Media, 2010. (In Russ.).
  16. Traverse-Glehen A., Verney A., Baseggio L. et al. Analysis of BCL-6, CD95, PIM1, RHO/TTF and PAX5 mutations in splenic and nodal marginal zone B-cell lymphomas suggests a particular B-cell origin Leukemia. Leukemia 2007;21(8):1821. doi: 10.1038/sj.leu.2404706.
  17. Ho L., Davis R.E., Conne B. et al. MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kBdependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 2005;105(7):2891–9. doi: 10.1182/blood-2004-06-2297.
  18. Sharpe A.H., Pauken K.E. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 2018 Mar;18(3):153–67. doi: 10.1038/nri.2017.108.
  19. Keir M.E., Butte M.J., Freeman G.J. et al. PD-1 and its ligands in tolerance and immunity. Ann Rev Immunol 2008;26: 677–704. doi: 10.1146/annurev.immunol.26.021607.090331.
  20. Freeman G.J., Long A.J., Iwai Y. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7):1027–34. doi: 10.1084/jem.192.7.1027.
  21. Dong H., Zhu G., Tamada K. et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5(12):1365–9. doi: 10.1038/70932.
  22. Armand P. Immune checkpoint blockade in hematologic malignancies. Blood 2015;125(22):3393–401. doi: 10.1182/blood-2015-02-567453.
  23. Upadhyay R., Hammerich L., Peng P. et al. Lymphoma: immune evasion strategies. Cancers (Basel) 2015;7(2): 736–62. doi: 10.3390/cancers7020736.
  24. Xia Y., Jeffrey Medeiros L., Young K.H. Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies. Biochim Biophys Acta 2016;1865(1):58–71. doi: 10.1016/j.bbcan.2015.09.002.
  25. Wherry E.J. T cell exhaustion. Nat Immunol 2011;12(6):492–9. doi: 10.1038/ni.2035.
  26. Riches J.C., Davies J.K., McClanahan F. et al. T cells from CLLpatients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013;121(9):1612–21. doi: 10.1182/blood-2012-09-457531.
  27. Barber D.L., Wherry E.J., Masopust D. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439(7077):682–7. doi: 10.1038/nature04444.
  28. Zenz T. Exhausting T cells in CLL. Blood 2013;121(9):1485–6. doi: 10.1182/blood-2013-01-475939.
  29. Wherry E.J., Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015;15(8):486–99. doi: 10.1038/nri3862.
  30. Jiang Y., Li Y., Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis 2015;6(6):e1792. doi: 10.1038/cddis.2015.162.
  31. Thieblemont C. Improved biological insight and influence on management in indolent lymphoma. Talk 3: Update on nodal and splenic marginal zone lymphoma. Hematology 2017;(1):371–8. doi: 10.1182/asheducation-2017.1.371.
  32. Wang K., Wei G., Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol 2012;1(1):36. doi: 10.1186/2162-3619-1-36.
  33. Mills D.M., Stolpa J.C., Cambier J.C. Modulation of MHC class II signal transduction by CD19. Adv Exp Med Biol 2007;596:139–48. doi: 10.1007/0-38746530-8_12.54.
  34. Martin F., Kearney J.F. B-cell subsets and the mature -preimmune repertoire. Marginal zone and B1 B cells as part of a “natural immune memory”. Immunol Rev 2000;175(1):70–9. doi: 10.1111/j.1600065X.2000.imr017515.x.
  35. Oliver A.M., Martin F., Kearney J.F. IgM high CD21 high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J Immunol 1999;162(12):7198–207. doi: 10.4049/jimmunol.170.5.2293.
  36. Zuccarino-Catania G.V., Sadanand S., Weisel F.J. et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat Immunol 2014;15(7):631–7. doi: 10.1038/ni.2914.
  37. Vincent-Fabert C., Soubeyran I., Saintamand A. et al. Splenic marginal zone B-cell lymphomas depends on programmed death-ligand 1 for clonal emergence and are controlled by T-cells for proliferation rate. Hematologica. Abstract PS1377.
  38. Morgan J.A., Yin Y., Borowsky A.D. et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res 1999;59(24):6205–13.
  39. Dierlamm J., Baens M., Wlodarska I. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999;93(11):3601–9.

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