Changes in the immune system in untreated patients with chronic lymphocytic leukaemia – part 2: innate immune system.
Authors:
P. Vodárek; L. Smolej; D. Belada; M. Šimkovič; D. Écsiová; P. Žák
Authors‘ workplace:
IV. interní hematologická klinika, Fakultní nemocnice a Univerzita Karlova v Praze, Lékařská fakulta v Hradci Králové
Published in:
Transfuze Hematol. dnes,27, 2021, No. 1, p. 1-19.
Category:
Overview
Chronic lymphocytic leukaemia (CLL), the most common leukaemia of adults in the western world, is associated with significant combined immunodeficiency. Besides changes in adaptive immunity, all components of innate immunity, both cellular i.e., NK cells, phagocytes and dendritic cells and humoral i.e., the complement cascade, can be affected. NK cells of CLL patients express less activation and more inhibitory receptors than those of healthy individuals. Together with changes in expression of these receptor ligands on CLL cells this prevents effective suppression of malignant clone proliferation by the immune system. Neutrophilic granulocytes have impaired ability of random migration, stimulated chemotaxis, respiratory burst or insufficient capacity of enzymes production and cytokine release. Other changes lead to the generation of so-called tumour associated neutrophils that suppress various cellular immunity components. Similarly, monocytes produce interleukin 10, transforming growth factor β and reactive oxygen species that lead to impairment of T-cell and NK cell function. Under the influence of CLL cells and regulatory T-cells, macrophages differentiate into nurse-like cells that attract CLL cells, support their survival and suppress non-regulatory T-cells. Dendritic cells are also affected by similar changes. Finally, complement defects can play a part in the development of not only infectious, but also autoimmune complications.
Keywords:
chronic – lymphocytic – leukaemia – immunodeficiency – cellular – humoral – NK – Granulocytes – Monocytes – Macrophages – dendritic – Complement – infections
Sources
1. Vodárek P, Smolej L, Belada D, Šimkovič M, Écsiová D, Žák P. Změny v imunitním systému u neléčených nemocných s chronickou lymfocytární leukemií – část 1: specifická imunita. Transfuze Hematol Dnes. 2021;27(2):128–136.
2. Kay NE, Zarling JM. Impaired natural killer activity in patients with chronic lymphocytic leukemia is associated with a deficiency of azurophilic cytoplasmic granules in putative NK cells. Blood. 1984;63(2):305–309.
3. Huergo-Zapico L, Acebes-Huerta A, Gonzalez-Rodriguez AP, et al. Expansion of NK cells and reduction of NKG2D expression in chronic lymphocytic leukemia. correlation with progressive disease. PLoS One. 2014;9(10):e108326
4. Parry HM, Stevens T, Oldreive C, et al. NK cell function is markedly impaired in patients with chronic lymphocytic leukaemia but is preserved in patients with small lymphocytic lymphoma. Oncotarget. 2016;7(42):68513–68526.
5. Veuillen C, Aurran-Schleinitz T, Castellano R, et al. Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy. J Clin Immunol. 2012;32(3):632–646.
6. Costello RT, Knoblauch B, Sanchez C, Mercier D, Le Treut T, Sébahoun G. Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia. Immunology. 2012;135(2):151–157.
7. Villa-Álvarez M, Sordo-Bahamonde C, Lorenzo-Herrero S, et al. Ig-like transcript 2 (ILT2) blockade and lenalidomide restore NK cell function in chronic lymphocytic leukemia. Front Immunol. 2018;9:2917.
8. Hadadi L, Hafezi M, Amirzargar AA, Sharifian, RA, Abediankenari S, Asgarian-Omran H. Dysregulated expression of Tim-3 and NKp30 receptors on NK cells of patients with chronic lymphocytic leukemia. Oncol Res Treat. 2019;42(4):202–208.
9. McWilliams EM, Mele JM, Cheney C, et al. Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia. Oncoimmunology. 2016;5(10):e1226720.
10. Hofland T, Endstra S, Gomes CKP, et al. Natural killer cell hypo-responsiveness in chronic lymphocytic leukemia can be circumvented in vitro by adequate activating signaling. Hemasphere. 2019;3(6):e308.
11. Reiners KS, Topolar D, Henke A, et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood. 2013;121(18):3658–3665.
12. MacFarlane AW 4th, Jillab M, Smith MR, et al. NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors. Oncoimmunology. 2017;6(7):e1330235.
13. Wang WT, Zhu HY, Wu YJ, et al. Elevated absolute NK cell counts in peripheral blood predict good prognosis in chronic lymphocytic leukemia. J Cancer Res Clin Oncol. 2018;144(3):449–457.
14. Sivori S, Meazza R, Quintarelli C, et al. NK cell-based immunotherapy for hematological malignancies. J Clin Med. 2019;8(10):1702.
15. Hofland T, Eldering E, Kater AP, Tonino SH. Engaging cytotoxic T and NK cells for immunotherapy in chronic lymphocytic leukemia. Int J Mol Sci. 2019;20(17):4315.
16. Levy I, Vadasz Z, Polliack A, Tadmor T. The frequency and prognostic value of neutrophilia in chronic lymphocytic leukemia. Anticancer Res. 2018;38(8):4731–4734.
17. Itälä M, Vainio O, Remes K. Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia. Eur J Haematol. 1996;57(1):46–53.
18. Zeya HI, Keku E, Richards F 2nd, Spurr Cl. Monocyte and granulocyte defect in chronic lymphocytic leukemia. Am J Pathol. 1979;95(1):43–54.
19. Kontoyiannis DP, Georgiadou SP, Wierda WG, et al. Impaired bactericidal but not fungicidal activity of polymorphonuclear neutrophils in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(8):1730–1733.
20. Manukyan G, Papajik T, Gajdos P, et al. Neutrophils in chronic lymphocytic leukemia are permanently activated and have functional defects. Oncotarget. 2017;8(49):84889–84901.
21. Podaza E, Risnik D, Colado A, et al. Chronic lymphocytic leukemia cells increase neutrophils survival and promote their differentiation into CD16high CD62Ldim immunosuppressive subset. Int J Cancer. 2019;144:1128–1134.
22. Podaza E, Sabbione F, Risnik D, et al. Neutrophils from chronic lymphocytic leukemia patients exhibit an increased capacity to release extracellular traps (NETs). Cancer Immunol Immunother. 2017;66(1):77–89.
23. Risnik D, Podaza E, Almejún MB, et al. Revisiting the role of interleukin-8 in chronic lymphocytic leukemia. Sci Rep. 2017;7(1):15714.
24. Blanco G, Puiggros A, Sherry B, et al. Chronic lymphocytic leukemia-like monoclonal B- cell lymphocytosis exhibits an increased inflammatory signature that is reduced in early-stage chronic lymphocytic leukemia. Exp Hematol. 2021;7:S0301-472X(21)00001-1.
25. Friedman DR, Sibley AB, Owzar K, et al. Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi-institutional study. Am J Hematol. 2016;91(7):687–691.
26. Maffei R, Bulgarelli J, Fiorcari S, et al. The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation. Haematologica. 2013;98(7):1115–1123.
27. Qorraj M, Bruns H, Böttcher M, et al. The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. Leukemia. 2017;31(2):470–478.
28. Seiffert M, Schulz A, Ohl S, Dohner H, Stilgenbauer S, Lichter P. Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at abnormally high levels in vivo. Blood. 2010;116(20):4223–4230.
29. Palumbo GA, Parrinello NL, Giallongo C, et al. Monocytic myeloid derived suppressor cells in hematological malignancies. Int J Mol Sci. 2019;20(21):5459.
30. Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.
31. Gustafson MP, Abraham RS, Lin Y, et al. Association of an increased frequency of CD14+ HLA-DR lo/neg monocytes with decreased time to progression in chronic lymphocytic leukaemia (CLL). Br J Haematol. 2012;156(5):674–676.
32. Jitschin R, Braun M, Büttner M, et al. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs. Blood. 2014;124(5):750–760.
33. Liu J, Zhou Y, Huang Q, Qiu L. CD14(+)HLA-DR(low/-) expression: A novel prognostic factor in chronic lymphocytic leukemia. Oncol Lett. 2015;9(3):1167–1172.
34. Petty AJ, Yang Y. Tumor-associated macrophages in hematologic malignancies: new insights and targeted therapies. Cells. 2019;8(12):1526.
35. Filip AA, Ciseł B, Koczkodaj D, Wasik-Szczepanek E, Piersiak T, Dmoszyńska A. Circulating microenvironment of CLL: are nurse-like cells related to tumor-associated macrophages? Blood Cells Mol Dis. 2013;50(4):263–270.
36. Giannoni P, Pietra G, Travaini G, et al. Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages. Haematologica. 2014;99(6):1078–1087.
37. Audrito V, Serra S, Brusa D, et al. Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia. Blood. 2015;125(1):111–123.
38. Van Attekum MHA, van Bruggen JAC, Slinger E, et al. CD40 signaling instructs chronic lymphocytic leukemia cells to attract monocytes via the CCR2 axis. Haematologica. 2017;102(12):2069–2076.
39. Boissard F, Fournié JJ, Laurent C, Poupot M, Ysebaert L. Nurse like cells: chronic lymphocytic leukemia associated macrophages. Leuk Lymphoma. 2015;56(5):1570–1572.
40. Brusa D, Serra S, Coscia M, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98(6):953–963.
41. Boissard F, Laurent C, Ramsay AG, et al. Nurse-like cells impact on disease progression in chronic lymphocytic leukemia. Blood Cancer J. 2016;6(1):e381.
42. Boissard F, Fournié JJ, Quillet-Mary A, Ysebaert L, Poupot M. Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients. Blood Cancer J. 2015;5(10):e355.
43. Galletti G, Scielzo C, Barbaglio F, et al. Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis. Cell Reports. 2016;14(7):1748–1760.
44. Rhodes JW, Tong O, Harman AN, Turville SG. Human dendritic cell subsets, ontogeny, and impact on HIV infection. Front Immunol. 2019;10:1088.
45. Saulep-Easton D, Vincent FB, Le Page M, et al. Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia. Leukemia. 2014;28(10):2005–2015.
46. Toniolo PA, Liu S, Yeh JE, Ye DQ, Barbuto JA, Frank DA. Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia. Oncotarget. 2016;7(29):46301–46314.
47. Barak AF, Lewinsky H, Perpinial M, et al. Bone marrow dendritic cells support the survival of chronic lymphocytic leukemia cells in a CD84 dependent manner. Oncogene. 2020;39(9):1997–2008.
48. Schlesinger M, Broman I, Lugassy G. The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives. Leukemia 1996;10(9):1509–1513.
49. Varga L, Czink E, Miszlai Z, et al. Low activity of the classical complement pathway predicts short survival of patients with chronic lymphocytic leukaemia. Clin Exp Immunol. 1995;99(1):112–116.
50. Michelis R, Tadmor T, Barhoum M, et al. A C5a-Immunoglobulin complex in chronic lymphocytic leukemia patients is associated with decreased complement activity. PLoS One. 2019;14(1):e0209024.
51. Michelis R, Tadmor T, Aviv A, et al. Cell-free IgG-aggregates in plasma of patients with chronic lymphocytic leukemia cause chronic activation of the classical complement pathway. PLoS One. 2020;15(3):e0230033.
52. Naseraldeen N, Michelis R, Barhoum M, et al. The Role of Alpha 2 Macroglobulin in IgG-Aggregation and Chronic Activation of the Complement System in Patients With Chronic Lymphocytic Leukemia. Front Immunol. 2021;11:603569.
53. Middleton O, Cosimo E, Dobbin E, et al. Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL. Leukemia. 2015;29:107–114.
54. Bordron A, Bagacean C, Mohr A, et al. Resistance to complement activation, cell membrane hypersialylation and relapses in chronic lymphocytic leukemia patients treated with rituximab and chemotherapy. Oncotarget. 2018;9(60):31590–31605.
55. García-Muñoz R, Roldan Galiacho V, Llorente L. Immunological aspects in chronic lymphocytic leukemia (CLL) development. Ann Hematol. 2012;91(7):981–996.
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Haematology Internal medicine Clinical oncologyArticle was published in
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