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Open Access 01-12-2015 | Research Article

T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment

Authors: Frauke M. Schnorfeil, Felix S. Lichtenegger, Katharina Emmerig, Miriam Schlueter, Julia S. Neitz, Rika Draenert, Wolfgang Hiddemann, Marion Subklewe

Published in: Journal of Hematology & Oncology | Issue 1/2015

Abstract

Background

T cell function is crucial for the success of several novel immunotherapeutic strategies for the treatment of acute myeloid leukemia (AML). However, changes in phenotype and function of T cells have been described in various hematologic malignancies, mimicking T cell exhaustion known from chronic viral infections. Detailed knowledge about phenotype and function of T cells in AML patients at different stages of the disease is indispensable for optimal development and application of immunotherapeutic strategies for this disease.

Methods

We used flow cytometry-based assays to characterize T cell phenotype and function in peripheral blood and bone marrow of AML patients at diagnosis, at relapse after intensive chemotherapy, and at relapse after allogeneic stem cell transplantation (SCT). Surface expression of CD244, PD-1, CD160, and TIM-3 was determined, and proliferation and production of IFN-γ, TNF-α, and IL-2 were measured.

Results

We detected similar expression of inhibitory molecules on T cells from patients at diagnosis and from age-matched healthy controls. At relapse after SCT, however, PD-1 expression was significantly increased compared to diagnosis, both on CD4⁺ and CD8⁺ T cells. This pattern was not associated with age and cytomegalovirus (CMV) status but with a shift towards effector memory cells in relapsed AML patients. Proliferation and cytokine production assays did not reveal functional defects in T cells of AML patients, neither at diagnosis nor at relapse.

Conclusion

We thus conclude that T cell exhaustion does not play a major role in AML. Immunotherapeutic strategies targeting autologous T cells thus have particularly good prospects in the setting of AML.

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Lichtenegger FS, Schnorfeil FM, Hiddemann W, Subklewe M. Current strategies in immunotherapy for acute myeloid leukemia. Immunotherapy. 2013;5(1):63–78.PubMedCrossRef

Lichtenegger FS, Krupka C, Köhnke T, Subklewe M. Immunotherapy for acute myeloid leukemia. Semin Hematol. 2015;52(3):207–14.PubMedCrossRef

Aigner M, Feulner J, Schaffer S, Kischel R, Kufer P, Schneider K, et al. T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct. Leukemia. 2012;27(5):1107–15.PubMedCrossRef

Krupka C, Kufer P, Kischel R, Zugmaier G, Bögeholz J, Köhnke T, et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood. 2014;123(3):356–65.PubMedCrossRef

Laszlo GS, Gudgeon CJ, Harrington KH, Dell’Aringa J, Newhall KJ, Means GD, et al. Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Blood. 2014;123(4):554–61.PubMedCentralPubMedCrossRef

Arndt C, von Bonin M, Cartellieri M, Feldmann A, Koristka S, Michalk I, et al. Redirection of T cells with a first fully humanized bispecific CD33-CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells. Leukemia. 2013;27(4):964–7.PubMedCrossRef

Mardiros A, Dos Santos C, McDonald T, Brown CE, Wang X, Budde LE, et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and anti-tumor effects against human acute myeloid leukemia. Blood. 2013;122(18):3138–48.PubMedCentralPubMedCrossRef

Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther. 2013;21(11):2122–9.PubMedCentralPubMedCrossRef

Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51.PubMedCrossRef

10.

Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6(1):74.PubMedCentralPubMedCrossRef

11.

Andersen MH. The targeting of immunosuppressive mechanisms in hematological malignancies. Leukemia. 2014;28(9):1784–92.PubMedCrossRef

12.

Shimauchi T, Kabashima K, Nakashima D, Sugita K, Yamada Y, Hino R, et al. Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4+ T-cells in adult T-cell leukemia/lymphoma. Int J Cancer. 2007;121(12):2585–90.PubMedCrossRef

13.

Kozako T, Yoshimitsu M, Fujiwara H, Masamoto I, Horai S, White Y, et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia. 2009;23(2):375–82.PubMedCrossRef

14.

Mumprecht S, Schürch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114(8):1528–36.PubMedCrossRef

15.

Christiansson L, Söderlund S, Svensson E, Mustjoki S, Bengtsson M, Simonsson B, et al. Increased level of myeloid-derived suppressor cells, programmed death receptor ligand 1/programmed death receptor 1, and soluble CD25 in Sokal high risk chronic myeloid leukemia. PLoS One. 2013;8(1), e55818.PubMedCentralPubMedCrossRef

16.

Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression. Clin Cancer Res. 2012;18(3):678–87.PubMedCrossRef

17.

Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612–21.PubMedCentralPubMedCrossRef

18.

Gassner FJ, Zaborsky N, Neureiter D, Huemer M, Melchardt T, Egle A, et al. Chemotherapy-induced augmentation of T cells expressing inhibitory receptors is reversed by treatment with lenalidomide in chronic lymphocytic leukemia. Haematologica. 2014;99(5):67–9.PubMedCentralPubMedCrossRef

19.

Wherry EJ. T cell exhaustion. Nat Immunol. 2011;131(6):492–9.CrossRef

20.

Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993;362(6422):758–61.PubMedCrossRef

21.

Gallimore A, Glithero A, Godkin A, Tissot AC, Plückthun A, Elliott T, et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med. 1998;187(9):1383–93.PubMedCentralPubMedCrossRef

22.

Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998;188(12):2205–13.PubMedCentralPubMedCrossRef

23.

Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–4.PubMedCrossRef

24.

Yamamoto T, Price DA, Casazza JP, Ferrari G, Nason M, Chattopadhyay PK, et al. Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection. Blood. 2011;117(18):4805–15.PubMedCentralPubMedCrossRef

25.

Peretz Y, He Z, Shi Y, Yassine-Diab B, Goulet JP, Bordi R, et al. CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathog. 2012;8(8), e1002840.PubMedCentralPubMedCrossRef

26.

Oxenius A, Zinkernagel RM, Hengartner H. Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity. 1998;9(4):449–57.PubMedCrossRef

27.

Brooks DG, Teyton L, Oldstone MB, McGavern DB. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J Virol. 2005;79(16):10514–27.PubMedCentralPubMedCrossRef

28.

Chlewicki LK, Velikovsky CA, Balakrishnan V, Mariuzza RA, Kumar V. Molecular basis of the dual functions of 2B4 (CD244). J Immunol. 2008;180(12):8159–67.PubMedCrossRef

29.

Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7.PubMedCrossRef

30.

Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51.PubMedCrossRef

31.

Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.PubMed

32.

Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol. 2008;9(2):176–85.PubMedCrossRef

33.

Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29–37.PubMedCentralPubMedCrossRef

34.

Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245–52.PubMedCrossRef

35.

Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205(12):2763–79.PubMedCentralPubMedCrossRef

36.

Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–86.PubMedCentralPubMedCrossRef

37.

Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–94.PubMedCentralPubMedCrossRef

38.

Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501–10.PubMedCentralPubMedCrossRef

39.

Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec G. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing. 2008;5:6.PubMedCentralPubMedCrossRef

40.

Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537–44.PubMedCentralPubMedCrossRef

41.

Baitsch L, Baumgaertner P, Devêvre E, Raghav SK, Legat A, Barba L, et al. Exhaustion of tumor-specific CD8⁺ T cells in metastases from melanoma patients. J Clin Invest. 2011;121(6):2350–60.PubMedCentralPubMedCrossRef

42.

Van den Hove LE, Vandenberghe P, Van Gool SW, Ceuppens JL, Demuynck H, Verhoef GE, et al. Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment. Leuk Res. 1998;22(2):175–84.PubMedCrossRef

43.

Le Dieu R, Taussig DC, Ramsay AG, Mitter R, Miraki-Moud F, Fatah R, et al. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood. 2009;114(18):3909–16.PubMedCentralPubMedCrossRef

44.

Lichtenegger FS, Lorenz R, Gellhaus K, Hiddemann W, Beck B, Subklewe M. Impaired NK cells and increased T regulatory cell numbers during cytotoxic maintenance therapy in AML. Leuk Res. 2014;38(8):964–9.PubMedCrossRef

45.

Wendelbo Ø, Nesthus I, Sjo M, Paulsen K, Ernst P, Bruserud Ø. Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapy-induced leukopenia. Cancer Immunol Immunother. 2004;53(8):740–7.PubMedCrossRef

46.

Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MG, et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res. 2011;71(15):5111–22.PubMedCrossRef

47.

Flörcken A, van Lessen A, Terwey TH, Dörken B, Arnold R, Pezzutto A, et al. Anti-leukemia T cells in AML: TNF-α⁺ CD8⁺ T cells may escape detection and possibly reflect a stage of functional impairment. Hum Vaccin Immunother. 2013;9(6):1200–4.PubMedCentralPubMedCrossRef

48.

Han S, Asoyan A, Rabenstein H, Nakano N, Obst R. Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery. Proc Natl Acad Sci U S A. 2010;107(47):20453–8.PubMedCentralPubMedCrossRef

49.

Antoine P, Olislagers V, Huygens A, Lecomte S, Liesnard C, Donner C, et al. Functional exhaustion of CD4+ T lymphocytes during primary cytomegalovirus infection. J Immunol. 2012;189(5):2665–72.PubMedCrossRef

50.

Dow C, Henderson R, Sette A, Mothé BR. CD4(+) T-cell inhibitory ligands: a tool for characterizing dysfunctional CD4(+) T cells during chronic infection. Immunology. 2013;140(1):61–9.PubMedCentralPubMedCrossRef

51.

Raimondi G, Shufesky WJ, Tokita D, Morelli AE, Thomson AW. Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells. J Immunol. 2006;176(5):2808–16.PubMedCrossRef

52.

Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, et al. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol. 2007;178(7):4112–9.PubMedCrossRef

53.

Legat A, Speiser DE, Pircher H, Zehn D, Fuertes Marraco SA. Inhibitory receptor expression depends more dominantly on differentiation and activation than “exhaustion” of human CD8 T cells. Front Immunol. 2013;4:455.PubMedCentralPubMedCrossRef

54.

Brusa D, Serra S, Coscia M, Rossi D, D’Arena G, Laurenti L, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013;98(6):953–63.PubMedCentralPubMedCrossRef

55.

Te Raa GD, Pascutti MF, García-Vallejo JJ, Reinen E, Remmerswaal EB, Ten Berge IJ, et al. CMV-specific CD8+ T cell function is not impaired in chronic lymphocytic leukemia. Blood. 2013;123(5):717–24.CrossRef

56.

Fredly H, Reikvam H, Gjertsen BT, Bruserud O. Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment. Am J Hematol. 2012;87(4):368–76.PubMedCrossRef

57.

Kornblau SM, McCue D, Singh N, Chen W, Estrov Z, Coombes KR. Recurrent expression signatures of cytokines and chemokines are present and are independently prognostic in acute myelogenous leukemia and myelodysplasia. Blood. 2010;116(20):4251–61.PubMedCentralPubMedCrossRef

58.

Lion E, Willemen Y, Berneman ZN, Van Tendeloo VF, Smits EL. Natural killer cell immune escape in acute myeloid leukemia. Leukemia. 2012;26(9):2019–26.PubMedCrossRef

Title: T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment
Authors: Frauke M. Schnorfeil
Felix S. Lichtenegger
Katharina Emmerig
Miriam Schlueter
Julia S. Neitz
Rika Draenert
Wolfgang Hiddemann
Marion Subklewe
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2015
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-015-0189-2

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