Impact of IL-1β and the IL-1R antagonist on relapse risk and survival in AML patients undergoing immunotherapy for remission maintenance

Hanna Grauers Wiktorin, Ebru Aydin, Karin Christenson, Nuttida Issdisai, Fredrik B Thorén, Kristoffer Hellstrand, Anna Martner, Hanna Grauers Wiktorin, Ebru Aydin, Karin Christenson, Nuttida Issdisai, Fredrik B Thorén, Kristoffer Hellstrand, Anna Martner

Abstract

Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, has been ascribed a role in the expansion of myeloid progenitors in acute myeloid leukemia (AML) and in promoting myeloid cell-induced suppression of lymphocyte-mediated immunity against malignant cells. This study aimed at defining the potential impact of IL-1β in the post-remission phase of AML patients receiving immunotherapy for relapse prevention in an international phase IV trial of 84 patients (ClinicalTrials.gov; NCT01347996). Consecutive serum samples were collected from AML patients in first complete remission (CR) who received cycles of relapse-preventive immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2). Low IL-1β serum levels before and after the first HDC/IL-2 treatment cycle favorably prognosticated leukemia-free survival and overall survival. Serum levels of IL-1β were significantly reduced in patients receiving HDC/IL-2. HDC also reduced the formation of IL-1β from activated human PBMCs in vitro. Additionally, high serum levels of the IL-1 receptor antagonist IL-1RA were associated with favorable outcome, and AML patients with low IL-1β along with high IL-1RA levels were strikingly protected against leukemic relapse. Our results suggest that strategies to target IL-1β might impact on relapse risk and survival in AML.

Keywords: Acute myeloid leukemia; IL-1RA; IL-1β; IL-2; NOX2; histamine; relapse preventive immunotherapy.

Conflict of interest statement

Authors HGW, KH and AM hold issued or pending patents protecting the use of NOX2 inhibitors in cancer. The other authors declare no potential conflicts of interest.

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.
Figure 1.
Serum IL-1βlevels are reduced following HDC/IL-2 immunotherapy. Serum levels of IL-1β (a) and IL-1RA (b) before (D1) and after (D21) cycles 1 (C1) and 3 (C3) of HDC/IL-2 immunotherapy (C1D1 n = 78, C1D21 n = 73, C3D1 n = 55, C3D21 n = 53; Wilcoxon-matched pairs test; * p < .05, ** p < .01). The production of IL-1β (c) and IL-1RA (d) by PBMCs stimulated with 0.5 µg/ml LPS in the presence or absence of HDC (100 µM), DPI (100 nM) or IL-2 (500 U/ml). Ctrl, LPS, LPS+HDC; n = 7, LPS+DPI and LPS+IL-2; n = 5; Mixed-effects analysis followed by Holm-Sidak’s multiple comparisons test; * p < .05, ** p < .01, *** p < .001
Figure 2.
Figure 2.
Low IL-1βand high IL-1RA serum levels after immunotherapy are associated with a favorable outcome in AML. (a-d) Patients dichotomized based on below or above 0.6 pg/ml of IL-1β (a, b) or 66 pg/ml IL-1RA (c-d) in serum after the first cycle of immunotherapy were analyzed for leukemia-free survival (a, c) or overall survival (b, d) by the log-rank test. (e-f) Patients were separated into three groups where the first constituted patients with low (<0.6 pg/ml) IL-1β levels along with high (>66 pg/ml) IL-1RA levels in serum after the first cycle of immunotherapy (IL-1β low and IL-1RA high, black line, n = 30), the second constituted patients with high IL-1β levels along with low IL-1RA levels (IL-1β high and IL-1RA low, blue line, n = 24), and the remaining patients were in the third group (IL-1β low or IL-1RA high, red line, n = 19). The leukemia-free survival (e) and overall survival (f) of patients in the three groups were analyzed by the log-rank test for trend

References

    1. Bertoli S, Tavitian S, Huynh A, Borel C, Guenounou S, Luquet I, Delabesse E, Sarry A, Laurent G, Attal M, et al. Improved outcome for AML patients over the years 2000-2014. Blood Cancer J. 2017;7(12):p. 635. doi:10.1038/s41408-017-0011-1.
    1. Döhner H, et al.. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):p. 424–9.
    1. Huls G, Chitu DA, Havelange V, Jongen-Lavrencic M, van de Loosdrecht AA, Biemond BJ, Sinnige H, Hodossy B, Graux C, Kooy RVM, et al.. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood. 2019;133(13):1457–1464. doi:10.1182/blood-2018-10-879866.
    1. Wei AH, et al.. The QUAZAR AML-001 Maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Washington (DC): American Society of Hematology; 2019
    1. Brune M, et al.. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood. 2006;108(1):88–96. doi:10.1182/blood-2005-10-4073.
    1. Martner A, Thorén FB, Aurelius J, Söderholm J, Brune M, Hellstrand K.. Immunotherapy with histamine dihydrochloride for the prevention of relapse in acute myeloid leukemia. Expert Rev Hematol. 2010;3(4):381–391. doi:10.1586/ehm.10.30.
    1. Martner A, Thorén FB, Aurelius J, Hellstrand K.. Immunotherapeutic strategies for relapse control in acute myeloid leukemia. Blood Rev. 2013;27(5):209–216. doi:10.1016/j.blre.2013.06.006.
    1. Binder S, Luciano M, Horejs-Hoeck J. The cytokine network in acute myeloid leukemia (AML): a focus on pro- and anti-inflammatory mediators. Cytokine Growth Factor Rev. 2018;43:8–15. doi:10.1016/j.cytogfr.2018.08.004.
    1. Turzanski J, et al.. Interleukin-1beta maintains an apoptosis-resistant phenotype in the blast cells of acute myeloid leukaemia via multiple pathways. Leukemia. 2004;18(10):1662–1670. doi:10.1038/sj.leu.2403457.
    1. Bruserud O. Effects of endogenous interleukin 1 on blast cells derived from acute myelogenous leukemia patients. Leuk Res. 1996;20(1):65–73. doi:10.1016/0145-2126(95)00112-3.
    1. Carey A, Edwards DK, Eide CA, Newell L, Traer E, Medeiros BC, Pollyea DA, Deininger MW, Collins RH, Tyner JW, et al.. Identification of interleukin-1 by functional screening as a key mediator of cellular expansion and disease progression in acute myeloid leukemia. Cell Rep. 2017;18(13):3204–3218. doi:10.1016/j.celrep.2017.03.018.
    1. Wang Y, Sun X, Yuan S, Hou S, Guo T, Chu Y, Pang T, Luo HR, Yuan W, Wang X, et al.. Interleukin-1β inhibits normal hematopoietic expansion and promotes acute myeloid leukemia progression via the bone marrow niche. Cytotherapy. 2020;22(3):127–134. doi:10.1016/j.jcyt.2020.01.001.
    1. Broudy VC. Stem cell factor and hematopoiesis. Blood. 1997;90:1345–1364.
    1. Wyszynski RW, Gibbs BF, Varani L, Iannotta D, Sumbayev VV. Interleukin-1 beta induces the expression and production of stem cell factor by epithelial cells: crucial involvement of the PI-3K/mTOR pathway and HIF-1 transcription complex. Cell Mol Immunol. 2016;13(1):47–56. doi:10.1038/cmi.2014.113.
    1. Lee SJ, Yoon JH, Song KS. Chrysin inhibited stem cell factor (SCF)/c-Kit complex-induced cell proliferation in human myeloid leukemia cells. Biochem Pharmacol. 2007;74(2):215–225. doi:10.1016/j.bcp.2007.04.011.
    1. Tao M, et al.. SCF, IL-1beta, IL-1ra and GM-CSF in the bone marrow and serum of normal individuals and of AML and CML patients. Cytokine. 2000;12(6):699–707. doi:10.1006/cyto.2000.0666.
    1. Fields JK, Günther S, Sundberg EJ. Structural basis of IL-1 family cytokine signaling. Front Immunol. 2019;10:1412. doi:10.3389/fimmu.2019.01412.
    1. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018;281:8–27.
    1. Loo YM, Gale M Jr.. Immune signaling by RIG-I-like receptors. Immunity. 2011;34(5):680–692. doi:10.1016/j.immuni.2011.05.003.
    1. Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009;10(3):241–247. doi:10.1038/ni.1703.
    1. Schreuder H, Tardif C, Trump-Kallmeyer S, Soffientini A, Sarubbi E, Akeson A, Bowlin T, Yanofsky S, Barrett RW. A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist. Nature. 1997;386(6621):194–200. doi:10.1038/386194a0.
    1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al.. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–1131. doi:10.1056/NEJMoa1707914.
    1. Kaplanov I, Carmi Y, Kornetsky R, Shemesh A, Shurin GV, Shurin MR, Dinarello CA, Voronov E, Apte RN. Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti–PD-1 for tumor abrogation. Proc Natl Acad Sci U S A. 2019;116(4):1361–1369. doi:10.1073/pnas.1812266115.
    1. Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity. 2019;50(4):778–795. doi:10.1016/j.immuni.2019.03.012.
    1. Lee P-H, Yamamoto TN, Gurusamy D, Sukumar M, Yu Z, Hu-Li J, Kawabe T, Gangaplara A, Kishton RJ, Henning AN, et al.. Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells. J Exp Med. 2019;216(11):2619–2634. doi:10.1084/jem.20181218.
    1. Aggen DH, Ager CR, Obradovic AZ, Chowdhury N, Ghasemzadeh A, Mao W, Chaimowitz MG, Lopez-Bujanda ZA, Spina CS, Hawley JE, et al.. Blocking IL1 beta promotes tumor regression and remodeling of the myeloid compartment in a renal cell carcinoma model: multidimensional analyses. Clin Cancer Res. 2021;27(2):608–621. doi:10.1158/1078-0432.CCR-20-1610.
    1. Sander FE, Rydström A, Bernson E, Kiffin R, Riise R, Aurelius J, Anderson H, Brune M, Foà R, Hellstrand K, et al.. Dynamics of cytotoxic T cell subsets during immunotherapy predicts outcome in acute myeloid leukemia. Oncotarget. 2016;7(7):7586–7596. doi:10.18632/oncotarget.7210.
    1. Martner A, Rydström A, Riise RE, Aurelius J, Anderson H, Brune M, Foà R, Hellstrand K, Thorén FB. Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia. Oncoimmunology. 2016;5(1):e1041701. doi:10.1080/2162402X.2015.1041701.
    1. Martner A, Rydström A, Riise RE, Aurelius J, Brune M, Foà R, Hellstrand K, Thorén FB. NK cell expression of natural cytotoxicity receptors may determine relapse risk in older AML patients undergoing immunotherapy for remission maintenance. Oncotarget. 2015;6(40):42569–42574. doi:10.18632/oncotarget.5559.
    1. Sander FE, et al.. Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy. Cancer Immunol Immunother. 2017;66(4):1473–1484. doi:10.1007/s00262-017-2040-9.
    1. Bai B, Yang Y, Wang Q, Li M, Tian C, Liu Y, Aung LHH, Li P-F, Yu T, Chu X-M, et al.. NLRP3 inflammasome in endothelial dysfunction. Cell Death Dis. 2020;11(9):776. doi:10.1038/s41419-020-02985-x.
    1. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;11(9):210–215. doi:10.1038/nri2725.
    1. Martner A, Wiktorin HG, Lenox B, Ewald Sander F, Aydin E, Aurelius J, Thorén FB, Ståhlberg A, Hermodsson S, Hellstrand K, et al.. Histamine promotes the development of monocyte-derived dendritic cells and reduces tumor growth by targeting the myeloid NADPH oxidase. J Immunol. 2015;194(10):5014–5021. doi:10.4049/jimmunol.1402991.
    1. Hellstrand K, Asea A, Dahlgren C, Hermodsson S. Histaminergic regulation of NK cells. Role of monocyte-derived reactive oxygen metabolites. J Immunol. 1994;153:4940–4947.
    1. Asea A, Hermodsson S, Hellstrand K. Histaminergic regulation of natural killer cell-mediated clearance of tumour cells in mice. Scand J Immunol. 1996;43(1):9–15. doi:10.1046/j.1365-3083.1996.d01-14.x.
    1. Hallner A, Bernson E, Hussein BA, Ewald Sander F, Brune M, Aurelius J, Martner A, Hellstrand K, Thorén FB. The HLA-B −21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia. Blood. 2019;133(13):1479–1488. doi:10.1182/blood-2018-09-874990.
    1. Bernson E, Hallner A, Sander FE, Nicklasson M, Nilsson MS, Christenson K, Aydin E, Liljeqvist J-Å, Brune M, Foà R, et al.. Cytomegalovirus serostatus affects autoreactive NK cells and outcomes of IL2-based immunotherapy in acute myeloid leukemia. Cancer Immunol Res. 2018;6(9):1110–1119. doi:10.1158/2326-6066.CIR-17-0711.
    1. Branco A, Yoshikawa FSY, et al.. Role of histamine in modulating the immune response and inflammation. Mediators Inflamm. 2018;2018:9524075. Pietrobon, A J., Sato, M N.. doi:10.1155/2018/9524075.
    1. Dohlsten M, et al.. Histamine inhibits interleukin 1 production by lipopolysaccharide-stimulated human peripheral blood monocytes. Scand J Immunol. 1988;27(5):527–532. doi:10.1111/j.1365-3083.1988.tb02379.x.
    1. Nishibori M, Takahashi HK, Mori S. The regulation of ICAM-1 and LFA-1 interaction by autacoids and statins: a novel strategy for controlling inflammation and immune responses. J Pharmacol Sci. 2003;92(1):7–12. doi:10.1254/jphs.92.7.
    1. Mellqvist UH, Hansson M, Brune M, Dahlgren C, Hermodsson S, Hellstrand K. Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine. Blood. 2000;96(5):1961–1968. doi:10.1182/blood.V96.5.1961.
    1. Aydin E, Johansson J, Nazir FH, Hellstrand K, Martner A. Role of NOX2-derived reactive oxygen species in NK cell-mediated control of murine melanoma metastasis. Cancer Immunol Res. 2017;5(9):804–811. doi:10.1158/2326-6066.CIR-16-0382.
    1. Frei R, Ferstl R, Konieczna P, Ziegler M, Simon T, Rugeles TM, Mailand S, Watanabe T, Lauener R, Akdis CA, et al.. Histamine receptor 2 modifies dendritic cell responses to microbial ligands. J Allergy Clin Immunol. 2013;132(1):194–204. doi:10.1016/j.jaci.2013.01.013.
    1. Yang XD, Ai W, Asfaha S, Bhagat G, Friedman RA, Jin G, Park H, Shykind B, Diacovo TG, Falus A, et al.. Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells. Nat Med. 2011;17(1):87–95. doi:10.1038/nm.2278.
    1. Haraldsen G, Kvale D, Lien B, Farstad IN, Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J Immunol. 1996;156:2558–2565.
    1. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KHG. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31(2):331–341. doi:10.1016/j.immuni.2009.08.001.
    1. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179–189. doi:10.1016/j.immuni.2006.01.001.
    1. Kramer F, Torzewski J, Kamenz J, Veit K, Hombach V, Dedio J, Ivashchenko Y. Interleukin-1beta stimulates acute phase response and C-reactive protein synthesis by inducing an NFkappaB- and C/EBPbeta-dependent autocrine interleukin-6 loop. Mol Immunol. 2008;45(9):2678–2689. doi:10.1016/j.molimm.2007.12.017.
    1. Kordella C, Lamprianidou E, Kotsianidis I. Mechanisms of action of hypomethylating agents: endogenous retroelements at the epicenter. Front Oncol. 2021;11:650473. doi:10.3389/fonc.2021.650473.
    1. Moudra A, Hubackova S, Machalova V, Vancurova M, Bartek J, Reinis M, Hodny Z, Jonasova A. Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine. Oncoimmunology. 2016;5(10):e1183860. doi:10.1080/2162402X.2016.1183860.
    1. Hashimoto K, Oreffo ROC, Gibson MB, Goldring MB, Roach HI. DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheum. 2009;60(11):3303–3313. doi:10.1002/art.24882.
    1. Martner A, Aydin E, Hellstrand K. NOX2 in autoimmunity tumor growth and metastasis. J Pathol. 2019;247(2):151–154. doi:10.1002/path.5175.
    1. Singh A, Singh V, Tiwari RL, Chandra T, Kumar A, Dikshit M, Barthwal MK. The IRAK-ERK-p67phox-Nox-2 axis mediates TLR4, 2-induced ROS production for IL-1β transcription and processing in monocytes. Cell Mol Immunol. 2016;13(6):745–763. doi:10.1038/cmi.2015.62.
    1. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320(5876):674–677. doi:10.1126/science.1156995.
    1. Gabelloni ML, et al.. NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL-1β secretion but not in inflammasome activation. Eur J Immunol. 2013;43(12):3324–3335. doi:10.1002/eji.201243089.
    1. Liu N, Wu Y, Wen X, Li P, Lu F, Shang H. Chronic stress promotes acute myeloid leukemia progression through HMGB1/NLRP3/IL-1β signaling pathway. J Mol Med (Berl). 2021;99(3):403–414. doi:10.1007/s00109-020-02011-9.
    1. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720–3732. doi:10.1182/blood-2010-07-273417.
    1. Aldieri E, Riganti C, Polimeni M, Gazzano E, Lussiana C, Campia I, Ghigo D. Classical inhibitors of NOX NAD(P)H oxidases are not specific. Curr Drug Metab. 2008;9(8):686–696. doi:10.2174/138920008786049285.
    1. Massart C, Giusti N, Beauwens R, Dumont JE, Miot F, Sande JV. Diphenyleneiodonium, an inhibitor of NOXes and DUOXes, is also an iodide-specific transporter. FEBS Open Bio. 2013;4(1):55–59. doi:10.1016/j.fob.2013.11.007.
    1. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, Ridker P, Lorenzatti A, Krum H, Varigos J, et al.. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833–1842. doi:10.1016/S0140-6736(17)32247-X.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir