Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients

Clinical and Experimental Immunology

Volumn 177, Issue 2, 2014, Pages 439-453

  Busch, A ^a   Zeh, D ^a   Janzen, V ^a   Mugge L O ^b   Wolf, D ^a   Fingerhut, L ^a   Hahn Ast, C ^a   Maurer, O ^a   Brossart, P ^a   von Lilienfeld Toal, M ^b,c  

^a UNIVERSITY HOSPITAL BONN   (Germany)

^b JENA UNIVERSITY HOSPITAL   (Germany)

^c HANS KNÖLL INSTITUTE   (Germany)

Author keywords

Immunoregulation; Lenalidomide; MDSCs; Multiple myeloma; T cells

Indexed keywords

CD14 ANTIGEN; CD15 ANTIGEN; CD8 ANTIGEN; GRANZYME; LENALIDOMIDE; PERFORIN;

ADULT; AGED; ANTIGEN EXPRESSION; ARTICLE; BONE MARROW CELL; CANCER PATIENT; CD8+ T LYMPHOCYTE; CLINICAL ARTICLE; CONTROLLED STUDY; EFFECTOR CELL; FEMALE; HUMAN; HUMAN CELL; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; IMMUNOREGULATION; IMMUNOSTIMULATION; IMMUNOSUPPRESSIVE TREATMENT; IN VITRO STUDY; LYMPHOCYTE PROLIFERATION; MALE; MEMORY T LYMPHOCYTE; MULTIPLE MYELOMA; MYELOID DERIVED SUPPRESSOR CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; SUPPRESSOR CELL; T LYMPHOCYTE SUBPOPULATION;

IMMUNOREGULATION; LENALIDOMIDE; MDSCS; MULTIPLE MYELOMA; T CELLS;

AGED; FEMALE; HUMANS; IMMUNOLOGIC FACTORS; IMMUNOLOGIC MEMORY; IMMUNOMODULATION; IMMUNOPHENOTYPING; LYMPHOCYTE ACTIVATION; MALE; MIDDLE AGED; MULTIPLE MYELOMA; MYELOID CELLS; PHENOTYPE; T-LYMPHOCYTE SUBSETS; THALIDOMIDE;

EID: 84903957798     PISSN: 00099104     EISSN: 13652249     Source Type: Journal    
DOI: 10.1111/cei.12343     Document Type: Article

References (46)

1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood 2008; 111:2962-2972.
2. Cook G, Campbell JD, Carr CE, Boyd KS, Franklin IM. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol 1999; 66:981-988.
3. Liu J, Hamrouni A, Wolowiec D etal. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007; 110:296-304.
4. Brown RD, Pope B, Murray A etal. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood 2001; 98:2992-2998.
5. Wang S, Yang J, Qian J, Wezeman M, Kwak LW, Yi Q. Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma. Blood 2006; 107:2432-2439.
6. Mozaffari F, Hansson L, Kiaii S etal. Signalling molecules and cytokine production in T cells of multiple myeloma-increased abnormalities with advancing stage. Br J Haematol 2004; 124:315-324.
7. Feyler S, von Lilienfeld-Toal M, Jarmin S etal. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) double negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol 2009; 144:686-695.
8. Beyer M, Kochanek M, Giese T etal. In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 2006; 107:3940-3949.
9. von Lilienfeld-Toal M, Frank S, Leyendecker C etal. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother 2010; 59:829-839.
10. Jinushi M, Vanneman M, Munshi NC etal. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA 2008; 105:1285-1290.
11. Peranzoni E, Zilio S, Marigo I etal. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 2010; 22:238-244.
12. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9:162-174.
13. Tadmor T, Attias D, Polliack A. Myeloid-derived suppressor cells-their role in haemato-oncological malignancies and other cancers and possible implications for therapy. Br J Haematol 2011; 153:557-567.
14. Brimnes MK, Vangsted AJ, Knudsen LM etal. Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand J Immunol 2010; 72:540-547.
15. Gorgun GT, Whitehill G, Anderson JL etal. Tumor promoting immune suppressive myeloid derived suppressor cells in multiple myeloma microenvironment. Blood 2013; 121:2975-2987.
16. Attal M, Lauwers-Cances V, Marit G etal. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366:1782-1791.
17. Verhelle D, Corral LG, Wong K etal. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 67:746-755.
18. Gandhi AK, Kang J, Capone L etal. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets 2010; 10:155-167.
19. Larocca A, Cavallo F, Mina R, Boccadoro M, Palumbo A. Current treatment strategies with lenalidomide in multiple myeloma and future perspectives. Future Oncol 2012; 8:1223-1238.
20. Weber DM, Chen C, Niesvizky R etal. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357:2133-2142.
21. Rajkumar SV, Hayman SR, Lacy MQ etal. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106:4050-4053.
22. De Keersmaecker B, Allard SD, Lacor P, Schots R, Thielemans K, Aerts JL. Expansion of polyfunctional HIV-specific T cells upon stimulation with mRNA electroporated dendritic cells in the presence of immunomodulatory drugs. J Virol 2012; 86:9351-9360.
23. Neuber B, Herth I, Tolliver C etal. Lenalidomide enhances antigen-specific activity and decreases CD45RA expression of T cells from patients with multiple myeloma. J Immunol 2011; 187:1047-1056.
24. Noonan K, Rudraraju L, Ferguson A etal. Lenalidomide-induced immunomodulation in multiple myeloma: impact on vaccines and antitumor responses. Clin Cancer Res 2012; 18:1426-1434.
25. Davies FE, Raje N, Hideshima T etal. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98:210-216.
26. Lioznov M, El-Cheikh J Jr, Hoffmann F etal. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant 2010; 45:349-353.
27. Wolschke C, Stubig T, Hegenbart U etal. Postallograft lenalidomide induces strong NK cell-mediated antimyeloma activity and risk for T cell-mediated GvHD: results from a phase I/II dose-finding study. Exp Hematol 2012; 41:134-142.
28. Kneppers E, van der Holt B, Kersten MJ etal. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. Blood 2011; 118:2413-2419.
29. Sockel K, Bornhaeuser M, Mischak-Weissinger E etal. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-versus-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial. Haematologica 2012; 97:e34-35.
30. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 2004; 22:745-763.
31. Appay V, van Lier RA, Sallusto F, Roederer M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A 2008; 73:975-983.
32. Volk HD, Thieme M, Heym S etal. Alterations in function and phenotype of monocytes from patients with septic disease-predictive value and new therapeutic strategies. In Faist E, Meakins JL, Schildberg FW, eds. Host defense dysfunction in trauma, shock, and sepsis. Berlin/Heidelberg, Germany: Springer-Verlag, 1993:365-371.
33. Asadullah K, Woiciechowsky C, Docke WD etal. Very low monocytic HLA-DR expression indicates high risk of infection-immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy. Eur J Emerg Med 1995; 2:184-190.
34. Turina M, Dickinson A, Gardner S, Polk HC Jr. Monocyte HLA-DR and interferon-gamma treatment in severely injured patients-a critical reappraisal more than a decade later. J Am Coll Surg 2006; 203:73-81.
35. Volk HD, Reinke P, Krausch D etal. Monocyte deactivation-rationale for a new therapeutic strategy in sepsis. Intensive Care Med 1996; 22 (Suppl. 4):S474-481.
36. Hoechst B, Ormandy LA, Ballmaier M etal. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008; 135:234-243.
37. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R. Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 2010; 70:4335-4345.
38. Hoechst B, Voigtlaender T, Ormandy L etal. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009; 50:799-807.
39. Filipazzi P, Valenti R, Huber V etal. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 2007; 25:2546-2553.
40. Vuk-Pavlovic S, Bulur PA, Lin Y etal. Immunosuppressive CD14+HLA-DRlow/- monocytes in prostate cancer. Prostate 2010; 70:443-455.
41. Luptakova K, Rosenblatt J, Glotzbecker B etal. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother 2012; 62:39-49.
42. McDaniel JM, Zou JX, Fulp W, Chen DT, List AF, Epling-Burnette PK. Reversal of T-cell tolerance in myelodysplastic syndrome through lenalidomide immune modulation. Leukemia 2012; 26:1425-1429.
43. Minnema MC, van der Veer MS, Aarts T, Emmelot M, Mutis T, Lokhorst HM. Lenalidomide alone or in combination with dexamethasone is highly effective in patients with relapsed multiple myeloma following allogeneic stem cell transplantation and increases the frequency of CD4+Foxp3+ T cells. Leukemia 2009; 23:605-607.
44. Galustian C, Meyer B, Labarthe MC etal. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 2009; 58:1033-1045.
45. Mandruzzato S, Solito S, Falisi E etal. IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 2009; 182:6562-6568.
46. Huang MC, Greig NH, Luo W etal. Preferential enhancement of older human T cell cytokine generation, chemotaxis, proliferation and survival by lenalidomide. Clin Immunol 2011; 138:201-211.