A small proportion of chronic myeloid leukemia patients treated with interferon-α (IFN-α) monotherapy are able to discontinue the treatment without disease relapse although residual leukemia cells are present. Recently, we showed that these patients have increased amount of NK-cells and a distinct blood cytokine profile. We now aimed to study the function of NK- and T-cells in order to understand the role of the immune system in maintaining the treatment response after IFN-α discontinuation. The study included 13 patients: 5 patients were still treated with IFN-α monotherapy (IFN-ON, median treatment time 163 months) and 8 had stopped the treatment successfully (IFN-OFF, median time without therapy 42 months). Detailed immunophenotype and cytokine production of NK- and T-cells was analyzed with flow cytometry. In addition, the cytotoxicity of NK-cells was studied using K562 as target cells and both the degranulation and direct killing was measured. Compared to healthy controls, IFN-OFF patients had increased proportion of CD4(+) effector memory (CCR7(-)CD45RA(-); median 23% vs. healthy 16%, p = 0.009) and CD8(+) central memory T-cells (CCR7(+)CD45RA(-); median 26% vs. healthy 14%, p = 0.004). Further, upon stimulation the IFN-γ/TNF-α cytokine secretion by CD4(+) T-cells was significantly enhanced in IFN-OFF patients (median 13.7% vs. healthy 7.8%, p = 0.01), and CD4+ effector and central memory cells were the main cytokine producers. No similar increase was observed in IFN-ON group (6.5%). In addition, the proportion of NK-cells was significantly increased in IFN-OFF patients (median IFN-OFF 24%, healthy 13%, p = 0.04), but their direct killing of K562 cells was impaired. The cytotoxicity of NK-cells was also diminished in IFN-ON patients. To conclude, in addition to elevated NK-cell count, IFN-OFF patients have increased amount of memory T-cells, which are able to induce strong cytokine response upon stimulation. This activity may contribute to the maintenance of prolonged remission after successful IFN-α discontinuation.

Department of Hemato Oncology Faculty Hospital Olomouc and Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Hematology Research Unit Helsinki Department of Medicine University of Helsinki and Helsinki University Central Hospital Helsinki Finland

Hospital de S Joao Porto Portugal

Zobrazit více v PubMed

Hehlmann R, Hochhaus A, Baccarani M (2007) Chronic myeloid leukaemia. Lancet 370: 342–350. PubMed

Deininger MW, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96: 3343–3356. PubMed

Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, et al. (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23: 1054–1061. PubMed

Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, et al. (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362: 2260–2270. PubMed

Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, et al. (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362: 2251–2259. PubMed

Simonsson B, Hjorth-Hansen H, Bjerrum OW, Porkka K (2011) Interferon alpha for treatment of chronic myeloid leukemia. Current Drug Targets 12: 420–428. PubMed

Talpaz M, Kantarjian H, Kurzrock R, Trujillo JM, Gutterman JU (1991) Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients. Ann Intern Med 114: 532–538. PubMed

Lee MS, Kantarjian H, Talpaz M, Freireich EJ, Deisseroth A, et al. (1992) Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy. Blood 79: 1920–1923. PubMed

Mahon FX, Delbrel X, Cony-Makhoul P, Faberes C, Boiron JM, et al. (2002) Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa. J Clin Oncol 20: 214–220. PubMed

Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, et al. (2001) Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 98: 3074–3081. PubMed

Deng M, Daley GQ (2001) Expression of interferon consensus sequence binding protein induces potent immunity against BCR/ABL-induced leukemia. Blood 97: 3491–3497. PubMed

Cortes J, Fayad L, Kantarjian H, O'Brien S, Lee MS, et al. (1998) Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia. Leukemia 12: 455–462. PubMed

Oka T, Sastry KJ, Nehete P, Schapiro SJ, Guo JQ, et al. (1998) Evidence for specific immune response against P210 BCR-ABL in long-term remission CML patients treated with interferon. Leukemia 12: 155–163. PubMed

Burchert A, Wolfl S, Schmidt M, Brendel C, Denecke B, et al. (2003) Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood 101: 259–264. PubMed

Simonsson B, Gedde-Dahl T, Markevarn B, Remes K, Stentoft J, et al. (2011) Combination of pegylated IFN-alpha2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood 118: 3228–3235. PubMed

O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, et al. (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348: 994–1004. PubMed

Wu SH, Zheng CP, Xu J (2012) [A retrospective study of chronic myelocytic leukemia treatment with imatinib and interferon-alpha]. Zhonghua Xue Ye Xue Za Zhi 33: 311–315. PubMed

Koskenvesa P KA, Rohon P, Pihlman M, Vakkila E et al... (2013) Imatinib and pegylated IFN-alpha2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response. Eur J Haematol. In press. PubMed

Burchert A, Muller MC, Kostrewa P, Erben P, Bostel T, et al. (2010) Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol 28: 1429–1435. PubMed

Kreutzman A, Rohon P, Faber E, Indrak K, Juvonen V, et al. (2011) Chronic myeloid leukemia patients in prolonged remission following interferon-alpha monotherapy have distinct cytokine and oligoclonal lymphocyte profile. PLoS One 6: e23022. PubMed PMC

Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, et al. (2010) Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363: 2511–2521. PubMed

Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, et al. (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11: 1029–1035. PubMed

Thielen N, van der Holt B, Cornelissen JJ, Verhoef GE, Gussinklo T, et al. (2013) Imatinib discontinuation in chronic phase myeloid leukaemia patients in sustained complete molecular response: a randomised trial of the Dutch-Belgian Cooperative Trial for Haemato-Oncology (HOVON). Eur J Cancer 49: 3242–3246. PubMed

Ilander M, Koskenvesa P, Hernesniemi S, Lion T, Porkka K, et al. (2013) Induction of sustained deep molecular response in a patient with chronic-phase T315I-mutated chronic myeloid leukemia with interferon-alpha monotherapy. Leuk Lymphoma 0: 1–4. PubMed

Itonaga H, Tsushima H, Hata T, Matsuo E, Imanishi D, et al. (2012) Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa. Int J Hematol 95: 209–213. PubMed

Powell DJ Jr, Dudley ME, Robbins PF, Rosenberg SA (2005) Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood 105: 241–250. PubMed PMC

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, et al. (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U S A 99: 16168–16173. PubMed PMC

Deng Y, Jing Y, Campbell AE, Gravenstein S (2004) Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol 172: 3437–3446. PubMed

Usuki K, Yokoyama K, Nagamura-Inoue T, Ito A, Kida M, et al. (2009) CD8+ memory T cells predominate over naive T cells in therapy-free CML patients with sustained major molecular response. Leuk Res 33: e164–165. PubMed

Yan J, Greer JM, Hull R, O'Sullivan JD, Henderson RD, et al. (2010) The effect of ageing on human lymphocyte subsets: comparison of males and females. Immun Ageing 7: 4. PubMed PMC

Keene JA, Forman J (1982) Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J Exp Med 155: 768–782. PubMed PMC

Braumuller H, Wieder T, Brenner E, Assmann S, Hahn M, et al. (2013) T-helper-1-cell cytokines drive cancer into senescence. Nature 494: 361–365. PubMed

Bennett SR, Carbone FR, Karamalis F, Miller JF, Heath WR (1997) Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J Exp Med 186: 65–70. PubMed PMC

Pawelec G, Da Silva P, Max H, Kalbacher H, Schmidt H, et al. (1995) Relative roles of natural killer- and T cell-mediated anti-leukemia effects in chronic myelogenous leukemia patients treated with interferon-alpha. Leuk Lymphoma 18: 471–478. PubMed

de Castro FA, Palma PV, Morais FR, Simoes BP, Carvalho PV, et al. (2003) Immunological effects of interferon-alpha on chronic myelogenous leukemia. Leuk Lymphoma 44: 2061–2067. PubMed

Sun H, Sun C, Xiao W (2014) Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations. Cytokine 65: 33–41. PubMed

Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, et al. (2010) CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood 116: 1299–1307. PubMed

Sun JC, Beilke JN, Bezman NA, Lanier LL (2011) Homeostatic proliferation generates long-lived natural killer cells that respond against viral infection. J Exp Med 208: 357–368. PubMed PMC

Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457: 557–561. PubMed PMC

Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, et al. (2012) Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119: 2665–2674. PubMed PMC

Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, et al. (2011) Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A 108: 14725–14732. PubMed PMC

Campbell KS, Hasegawa J (2013) Natural killer cell biology: an update and future directions. J Allergy Clin Immunol 132: 536–544. PubMed PMC

Promises and Challenges of Immunogenic Chemotherapy in Multiple Myeloma

Prognostic and Predictive Value of DAMPs and DAMP-Associated Processes in Cancer