Alterations of T-cell-mediated immunity in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a systemic, heterogeneous hematologic malignancy with poor overall survival. While some malignancies have seen improvements in clinical outcomes with immunotherapy, success of these agents in AML remains elusive. Despite limited progress, stem cell transplantation and donor lymphocyte infusions show that modulation of the immune system can improve overall survival of AML patients. Understanding the causes of immune evasion and disease progression will identify potential immune-mediated targets in AML. This review explores immunosuppressive mechanisms that alter T-cell-mediated immunity in AML.

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Fig. 1: Proposed mechanisms of T-cell suppression and promotion of T-cell dysfunction by AML.

References

  1. 1.

    Howlader NNA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, et al. SEER Cancer Statistics Review, 1975–2016. Bethesda, MD: National Cancer Institute.

  2. 2.

    Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21. https://doi.org/10.1056/NEJMoa1516192.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Pollyea DA. New drugs for acute myeloid leukemia inspired by genomics and when to use them. Hematology. 2018;2018:45–50. https://doi.org/10.1182/asheducation-2018.1.45.

    Article  PubMed  Google Scholar 

  4. 4.

    Cerrano M, Itzykson R. New treatment options for acute myeloid leukemia in 2019. Curr Oncol Rep. 2019;21:16. https://doi.org/10.1007/s11912-019-0764-8.

    Article  PubMed  Google Scholar 

  5. 5.

    Lamble AJ, Lind EF. Targeting the immune microenvironment in acute myeloid leukemia: a focus on T cell immunity. Front Oncol. 2018;8:213. https://doi.org/10.3389/fonc.2018.00213.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Austin R, Smyth MJ, Lane SW. Harnessing the immune system in acute myeloid leukaemia. Crit Rev Oncol/Hematol. 2016;103:62–77. https://doi.org/10.1016/j.critrevonc.2016.04.020.

    Article  Google Scholar 

  7. 7.

    Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.

    CAS  Article  Google Scholar 

  8. 8.

    Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk lymphoma. 2018;59:790–802. https://doi.org/10.1080/10428194.2017.1344905.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Liu Y, Bewersdorf JP, Stahl M, Zeidan AM. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: the dawn of a new era? Blood Rev. 2019;34:67–83. https://doi.org/10.1016/j.blre.2018.12.001.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Buggins AG, Milojkovic D, Arno MJ, Lea NC, Mufti GJ, Thomas NS. et al. Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappaB, c-Myc, and pRb pathways. J Immunol. 2001;167:6021–30.

    CAS  Article  Google Scholar 

  11. 11.

    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;114:3909–16. https://doi.org/10.1182/blood-2009-02-206946.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Barosi G. An immune dysregulation in MPN. Curr Hematol Malig Rep. 2014;9:331–9. https://doi.org/10.1007/s11899-014-0227-0.

    Article  PubMed  Google Scholar 

  13. 13.

    Fozza C, Crobu V, Isoni MA, Dore F. The immune landscape of myelodysplastic syndromes. Crit Rev Oncol/Hematol. 2016;107:90–9. https://doi.org/10.1016/j.critrevonc.2016.08.016.

    Article  Google Scholar 

  14. 14.

    Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34 https://doi.org/10.1186/s13073-017-0424-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Klco JM, Spencer DH, Miller CA, Griffith M, Lamprecht TL, O’Laughlin M, et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014;25:379–92. https://doi.org/10.1016/j.ccr.2014.01.031.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Hersh EM, Whitecar JP Jr., McCredie KB, Bodey GP Sr., Freireich EJ. Chemotherapy, immunocompetence, immunosuppression and prognosis in acute leukemia. N Engl J Med 1971;285:1211–6. https://doi.org/10.1056/nejm197111252852201.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Hersh EM, Gutterman JU, Mavligit GM, McCredie KB, Burgess MA, Matthews A, et al. Serial studies of immunocompetence of patients undergoing chemotherapy for acute leukemia. J Clin Investig. 1974;54:401–8. https://doi.org/10.1172/jci107775.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Rashidi A, Fisher SI. Spontaneous remission of acute myeloid leukemia. Leuk lymphoma. 2015;56:1727–34. https://doi.org/10.3109/10428194.2014.970545.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Muller-Schmah C, Solari L, Weis R, Pfeifer D, Scheibenbogen C, Trepel M, et al. Immune response as a possible mechanism of long-lasting disease control in spontaneous remission of MLL/AF9-positive acute myeloid leukemia. Ann Hematol. 2012;91:27–32. https://doi.org/10.1007/s00277-011-1332-y.

    Article  PubMed  Google Scholar 

  20. 20.

    Hasegawa K, Tanaka S, Fujiki F, Morimoto S, Nakajima H, Tatsumi N, et al. An immunocompetent mouse model for MLL/AF9 leukemia reveals the potential of spontaneous cytotoxic T-cell response to an antigen expressed in leukemia cells. PLoS ONE. 2015;10:e0144594. https://doi.org/10.1371/journal.pone.0144594.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Zhang L, Chen X, Liu X, Kline DE, Teague RM, Gajewski TF, et al. CD40 ligation reverses T cell tolerance in acute myeloid leukemia. J Clin Investig. 2013;123:1999–2010. https://doi.org/10.1172/jci63980.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Almosailleakh M, Schwaller J. Murine models of acute myeloid leukaemia. Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms20020453.

  23. 23.

    Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307. https://doi.org/10.1038/nri1806.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Teague RM, Kline J. Immune evasion in acute myeloid leukemia: current concepts and future directions. J Immunother Cancer. 2013;1. https://doi.org/10.1186/2051-1426-1-13.

  25. 25.

    Wang X, Zheng J, Liu J, Yao J, He Y, Li X, et al. Increased population of CD4(+)CD25(high), regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients. Eur J Haematol. 2005;75:468–76. https://doi.org/10.1111/j.1600-0609.2005.00537.x. e-pub ahead of print.

    Article  PubMed  Google Scholar 

  26. 26.

    Tian T, Yu S, Liu L, Xue F, Yuan C, Wang M, et al. The profile of T helper subsets in bone marrow microenvironment is distinct for different stages of acute myeloid leukemia patients and chemotherapy partly ameliorates these variations. PLoS ONE. 2015; 10. https://doi.org/10.1371/journal.pone.0131761.

  27. 27.

    Williams P, Basu S, Garcia-Manero G, Hourigan CS, Oetjen KA, Cortes JE, et al. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer. 2018. https://doi.org/10.1002/cncr.31896.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    van Galen P, Hovestadt V, Wadsworth Ii MH, Hughes TK, Griffin GK, Battaglia S, et al. Single-cell RNA-Seq reveals AML hierarchies relevant to disease progression and immunity. Cell. 2019;176:1265–81.e1224. https://doi.org/10.1016/j.cell.2019.01.031.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Ustun C, Miller JS, Munn DH, Weisdorf DJ, Blazar BR. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? Blood. 2011;118:5084–95. https://doi.org/10.1182/blood-2011-07-365817.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ersvaer E, Liseth K, Skavland J, Gjertsen BT, Bruserud O. Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and TREG cells. BMC Immunol. 2010;11:38. https://doi.org/10.1186/1471-2172-11-38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kanakry CG, Hess AD, Gocke CD, Thoburn C, Kos F, Meyer C, et al. Early lymphocyte recovery after intensive timed sequential chemotherapy for acute myelogenous leukemia: peripheral oligoclonal expansion of regulatory T cells. Blood. 2011;117:608–17. https://doi.org/10.1182/blood-2010-04-277939.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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;38:964–9. https://doi.org/10.1016/j.leukres.2014.05.014.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Shenghui Z, Yixiang H, Jianbo W, Kang Y, Laixi B, Yan Z, et al. Elevated frequencies of CD4(+) CD25(+) CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int J Cancer. 2011;129:1373–81. https://doi.org/10.1002/ijc.25791.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Szczepanski MJ, Szajnik M, Czystowska M, Mandapathil M, Strauss L, Welsh A. et al. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res. 2009;15:3325–32. https://doi.org/10.1158/1078-0432.Ccr-08-3010.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zhou Q, Bucher C, Munger ME, Highfill SL, Tolar J, Munn DH, et al. Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia. Blood. 2009;114:3793–802. https://doi.org/10.1182/blood-2009-03-208181.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kittang AO, Kordasti S, Sand KE, Costantini B, Kramer AM, Perezabellan P, et al. Expansion of myeloid derived suppressor cells correlates with number of T regulatory cells and disease progression in myelodysplastic syndrome. Oncoimmunology. 2016;5:e1062208. https://doi.org/10.1080/2162402x.2015.1062208.

    Article  PubMed  Google Scholar 

  37. 37.

    Menter T, Kuzmanic B, Bucher C, Medinger M, Halter J, Dirnhofer S, et al. Beneficial role of increased FOXP3(+) regulatory T-cells in acute myeloid leukaemia therapy response. Br J Haematol. 2018;182:581–3. https://doi.org/10.1111/bjh.14819.

    Article  PubMed  Google Scholar 

  38. 38.

    Schnorfeil FM, Lichtenegger FS, Emmerig K, Schlueter M, Neitz JS, Draenert R, et al. 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. J Hematol Oncol. 2015;8:93. https://doi.org/10.1186/s13045-015-0189-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sun YX, Kong HL, Liu CF, Yu S, Tian T, Ma DX, et al. The imbalanced profile and clinical significance of T helper associated cytokines in bone marrow microenvironment of the patients with acute myeloid leukemia. Hum Immunol. 2014;75:113–8. https://doi.org/10.1016/j.humimm.2013.11.014.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Musuraca G, De Matteis S, Napolitano R, Papayannidis C, Guadagnuolo V, Fabbri F, et al. IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia. J Transl Med. 2015;13:229. https://doi.org/10.1186/s12967-015-0590-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Tian T, Yu S, Wang M, Yuan C, Zhang H, Ji C. et al. Aberrant T helper 17 cells and related cytokines in bone marrow microenvironment of patients with acute myeloid leukemia. Clin Dev Immunol. 2013;2013:915873. https://doi.org/10.1155/2013/915873.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Han Y, Ye A, Bi L, Wu J, Yu K, Zhang S. Th17 cells and interleukin-17 increase with poor prognosis in patients with acute myeloid leukemia. Cancer Sci. 2014;105:933–42. https://doi.org/10.1111/cas.12459.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y, et al. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol. 2009;158:199–204. https://doi.org/10.1111/j.1365-2249.2009.04011.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.

    CAS  Article  Google Scholar 

  45. 45.

    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;117:4501–10. https://doi.org/10.1182/blood-2010-10-310425.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, et al. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature. 2018;562:605–9. https://doi.org/10.1038/s41586-018-0615-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    LaBelle JL, Hanke CA, Blazar BR, Truitt RL. Negative effect of CTLA-4 on induction of T-cell immunity in vivo to B7-1+, but not B7-2+, murine myelogenous leukemia. Blood. 2002;99:2146–53.

    CAS  Article  Google Scholar 

  48. 48.

    Knaus HA, Berglund S, Hackl H, Blackford AL, Zeidner JF, Montiel-Esparza R, et al. Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. JCI Insight. 2018;3. https://doi.org/10.1172/jci.insight.120974.

  49. 49.

    Wang M, Bu J, Zhou M, Sido J, Lin Y, Liu G. et al. CD8(+)T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients. Clin Immunol. 2018;190:64–73. https://doi.org/10.1016/j.clim.2017.08.021.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Dama P, Tang M, Fulton N, Kline J, Liu H. Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy. J Immunother Cancer. 2019;7:175. https://doi.org/10.1186/s40425-019-0611-3.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012;338:1220–5. https://doi.org/10.1126/science.1229620.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Jia B, Wang L, Claxton DF, Ehmann WC, Rybka WB, Mineishi S, et al. Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients. Blood Cancer J. 2018;8:34. https://doi.org/10.1038/s41408-018-0069-4.

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Jia B, Zhao C, Rakszawski KL, Claxton DF, Ehmann WC, Rybka WB, et al. Eomes+T-betlow CD8+ T cells are functionally impaired and are associated with poor clinical outcome in patients with acute myeloid leukemia (AML). Cancer Res. 2019. https://doi.org/10.1158/0008-5472.Can-18-3107.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study. Cancer Discov. 2019;9:370–83. https://doi.org/10.1158/2159-8290.Cd-18-0774.

    Article  PubMed  Google Scholar 

  55. 55.

    Masarova L, Kantarjian H, Ravandi F, Sharma P, Garcia-Manero G, Daver N. Update on immunotherapy in AML and MDS: monoclonal antibodies and checkpoint inhibitors paving the road for clinical practice. In: Naing A, Hajjar J, editors. Immunotherapy. Cham: Springer International Publishing; 2018. p. 97–116.

  56. 56.

    Lee JB, Chen B, Vasic D, Law AD, Zhang L. Cellular immunotherapy for acute myeloid leukemia: how specific should it be? Blood Rev. 2019;35:18–31. https://doi.org/10.1016/j.blre.2019.02.001.

    Article  PubMed  Google Scholar 

  57. 57.

    Wouters BJ, Delwel R. Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood. 2016;127:42–52. https://doi.org/10.1182/blood-2015-07-604512.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Kelderman S, Schumacher TN, Haanen JB. Acquired and intrinsic resistance in cancer immunotherapy. Mol Oncol. 2014;8:1132–9. https://doi.org/10.1016/j.molonc.2014.07.011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature. 2017;545:452–6. https://doi.org/10.1038/nature22367.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Radpour R, Riether C, Simillion C, Hopner S, Bruggmann R, Ochsenbein AF CD8(+) T cells expand stem and progenitor cells in favorable but not adverse risk acute myeloid leukemia. Leukemia 2019. https://doi.org/10.1038/s41375-019-0441-9.

  61. 61.

    Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196:459–68.

    CAS  Article  Google Scholar 

  62. 62.

    Curti A, Aluigi M, Pandolfi S, Ferri E, Isidori A, Salvestrini V, et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia. 2007;21:353–5. https://doi.org/10.1038/sj.leu.2404485.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Fukuno K, Hara T, Tsurumi H, Shibata Y, Mabuchi R, Nakamura N. et al. Expression of indoleamine 2,3-dioxygenase in leukemic cells indicates an unfavorable prognosis in acute myeloid leukemia patients with intermediate-risk cytogenetics. Leuk Lymphoma. 2015;56:1398–405. https://doi.org/10.3109/10428194.2014.953150.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Chamuleau ME, van de Loosdrecht AA, Hess CJ, Janssen JJ, Zevenbergen A, Delwel R, et al. High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica. 2008;93:1894–8. https://doi.org/10.3324/haematol.13113.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Corm S, Berthon C, Imbenotte M, Biggio V, Lhermitte M, Dupont C, et al. Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients’ sera by HPLC and is inducible by IFN-gamma. Leuk Res. 2009;33:490–4. https://doi.org/10.1016/j.leukres.2008.06.014.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood. 2007;109:2871–7. https://doi.org/10.1182/blood-2006-07-036863.

    CAS  Article  Google Scholar 

  67. 67.

    Arandi N, Ramzi M, Safaei F, Monabati A. Overexpression of indoleamine 2,3-dioxygenase correlates with regulatory T cell phenotype in acute myeloid leukemia patients with normal karyotype. Blood Res. 2018;53:294–8. https://doi.org/10.5045/br.2018.53.4.294.

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Mussai F, De Santo C, Abu-Dayyeh I, Booth S, Quek L, McEwen-Smith RM, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood. 2013;122:749–58. https://doi.org/10.1182/blood-2013-01-480129.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Mussai F, Wheat R, Sarrou E, Booth S, Stavrou V, Fultang L, et al. Targeting the arginine metabolic brake enhances immunotherapy for leukaemia. Int J Cancer. 2018. https://doi.org/10.1002/ijc.32028.

  70. 70.

    Orleans-Lindsay JK, Barber LD, Prentice HG, Lowdell MW. Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function–implications for the adoptive immunotherapy of leukaemia. Clin Exp Immunol. 2001;126:403–11.

    CAS  Article  Google Scholar 

  71. 71.

    Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–5.

    CAS  Article  Google Scholar 

  72. 72.

    Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31:272–81. https://doi.org/10.1038/leu.2016.275.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013;121:4917–24. https://doi.org/10.1182/blood-2013-03-493197.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018;24:1192–203. https://doi.org/10.1038/s41591-018-0095-6.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Zhang L, Sorensen MD, Kristensen BW, Reifenberger G, McIntyre TM, Lin F. D-2-hydroxyglutarate is an intercellular mediator in IDH-mutant gliomas inhibiting complement and T cells. Clin Cancer Res. 2018;24:5381–91. https://doi.org/10.1158/1078-0432.Ccr-17-3855.

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Xu T, Stewart KM, Wang X, Liu K, Xie M, Ryu JK, et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature. 2017;548:228–33. https://doi.org/10.1038/nature23475.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Kang X, Kim J, Deng M, John S, Chen H, Wu G. et al. Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors. Cell Cycle. 2016;15:25–40. https://doi.org/10.1080/15384101.2015.1121324.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Dobrowolska H, Gill KZ, Serban G, Ivan E, Li Q, Qiao P, et al. Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation. Cytom Part B Clin Cytom. 2013;84:21–9. https://doi.org/10.1002/cyto.b.21050.

    CAS  Article  Google Scholar 

  79. 79.

    Tonks A, Hills R, White P, Rosie B, Mills KI, Burnett AK, et al. CD200 as a prognostic factor in acute myeloid leukaemia. Leukemia. 2007;21:566–8. https://doi.org/10.1038/sj.leu.2404559.

    CAS  Article  Google Scholar 

  80. 80.

    Damiani D, Tiribelli M, Raspadori D, Sirianni S, Meneghel A, Cavalllin M, et al. Clinical impact of CD200 expression in patients with acute myeloid leukemia and correlation with other molecular prognostic factors. Oncotarget. 2015;6:30212–21. https://doi.org/10.18632/oncotarget.4901.

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Zahran AM, Mohammed Saleh MF, Sayed MM, Rayan A, Ali AM, Hetta HF. Up-regulation of regulatory T cells, CD200 and TIM3 expression in cytogenetically normal acute myeloid leukemia. Cancer Biomark. 2018;22:587–95. https://doi.org/10.3233/cbm-181368.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Coles SJ, Hills RK, Wang EC, Burnett AK, Man S, Darley RL, et al. Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells. Leukemia. 2012;26:2146–8. https://doi.org/10.1038/leu.2012.75.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Coles SJ, Hills RK, Wang EC, Burnett AK, Man S, Darley RL, et al. Expression of CD200 on AML blasts directly suppresses memory T-cell function. Leukemia. 2012;26:2148–51.

    CAS  Article  Google Scholar 

  84. 84.

    Moreaux J, Hose D, Reme T, Jourdan E, Hundemer M, Legouffe E, et al. CD200 is a new prognostic factor in multiple myeloma. Blood. 2006;108:4194–7. https://doi.org/10.1182/blood-2006-06-029355.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Moreaux J, Veyrune JL, Reme T, De Vos J, Klein B. CD200: a putative therapeutic target in cancer. Biochem Biophys Res Commun. 2008;366:117–22. https://doi.org/10.1016/j.bbrc.2007.11.103.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Kretz-Rommel A, Qin F, Dakappagari N, Ravey EP, McWhirter J, Oltean D. et al. CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy. J Immunol. 2007;178:5595–605. https://doi.org/10.4049/jimmunol.178.9.5595.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Kawasaki BT, Farrar WL. Cancer stem cells, CD200 and immunoevasion. Trends Immunol. 2008;29:464–8. https://doi.org/10.1016/j.it.2008.07.005.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Christopher MJ, Petti AA, Rettig MP, Miller CA, Chendamarai E, Duncavage EJ, et al. Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N. Engl J Med. 2018;379:2330–41. https://doi.org/10.1056/NEJMoa1808777.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Tikhonova AN, Dolgalev I, Hu H, Sivaraj KK, Hoxha E, Cuesta-Domínguez Á, et al. The bone marrow microenvironment at single-cell resolution. Nature 2019. https://doi.org/10.1038/s41586-019-1104-8.

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Acknowledgements

The authors are supported by K23HL138291(PBF) and T32CA217834 (ZL).

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Correspondence to P. Brent Ferrell.

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PBF receives research funding support from Incyte, Forma Therapeutics, and Astex Pharmaceuticals and has consulted for Agios Pharmaceuticals. ZL and MP have no competing interests to declare.

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Li, Z., Philip, M. & Ferrell, P.B. Alterations of T-cell-mediated immunity in acute myeloid leukemia. Oncogene 39, 3611–3619 (2020). https://doi.org/10.1038/s41388-020-1239-y

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