Chronic lymphocytic leukemia

T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease?


Chronic lymphocytic leukemia (CLL) is a B-cell malignancy, which is associated with profound alterations and defects in the immune system and a prevalent dependency on the microenvironmental niche. An abnormal T-cell compartment in the blood of CLL patients was already reported 40 years ago. Since then, our knowledge of T-cell characteristics in CLL has grown steadily, but the question of whether T-cells act as pro-tumoral bystander cells or possess anti-tumoral activity is still under debate. Increased numbers of CD4+ T-helper cell subsets are present in the blood of CLL patients, and T-helper cell cytokines have been shown to stimulate CLL cell survival and proliferation in vitro. In line with this, survival and growth of CLL cells in murine xenograft models have been shown to rely on activated CD4+ T-cells. This led to the hypothesis that T-cells are tumor-supportive in CLL. In recent years, evidence for an enrichment of antigen-experienced CD8+ T-cells in CLL has accumulated, and these cells have been shown to control leukemia in a CLL mouse model. Based on this, it was suggested that CD8+ T-cells recognize CLL-specific antigens and exert an anti-leukemia function. As described for other cancer entities, T-cells in CLL express multiple inhibitory receptors, such as PD-1, and lose their functional capacity, leading to an exhaustion phenotype which has been shown to be more severe in T-cells from secondary lymphoid organs compared with peripheral blood. This exhausted phenotype has been suggested to be causative for the poor response of CLL patients to CAR T-cell therapies. In addition, T-cells have been shown to be affected by drugs that are used to treat CLL, which likely impacts therapy response. This review provides an overview of the current knowledge about alterations of T-cells in CLL, including their distribution, function, and exhaustion state in blood and lymphoid organs, and touches also on the topic of how CLL drugs impact on the T-cell compartment and recent results of T-cell-based immunotherapy. We will discuss potential pathological roles of T-cell subsets in CLL and address the question of whether they foster progression or control of disease.

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Fig. 1: CD4+ T-cell subset diversity and distribution in CLL.
Fig. 2: Comparison of CD8+ T-cells from blood of CLL patients and healthy controls.
Fig. 3: T-cell exhaustion phenotype of CD8+ T-cells in blood versus lymph nodes of CLL patients.


  1. 1.

    Jelley-Gibbs DM, Strutt TM, McKinstry KK, Swain SL. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunol Cell Biol. 2008;86:343–52.

    CAS  PubMed  Google Scholar 

  2. 2.

    Appay V, van Lier RA, Sallusto F, Roederer M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytom Part A: J Int Soc Anal Cytol. 2008;73:975–83.

    Google Scholar 

  3. 3.

    King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol. 2008;26:741–66.

    CAS  PubMed  Google Scholar 

  4. 4.

    Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T Cell therapy in transplantation and autoimmunity. Front Immunol. 2019;10:43.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Takeuchi A, Saito T. CD4 CTL, a cytotoxic subset of CD4(+) T Cells, their differentiation and function. Front Immunol. 2017;8:194.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Elston L, Fegan C, Hills R, Hashimdeen SS, Walsby E, Henley P, et al. Increased frequency of CD4(+) PD-1(+) HLA-DR(+) T cells is associated with disease progression in CLL. British J. Haematol. 2020;188:872–80.

    CAS  Google Scholar 

  7. 7.

    Palma M, Gentilcore G, Heimersson K, Mozaffari F, Nasman-Glaser B, Young E, et al. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica. 2017;102:562–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Catakovic K, Gassner FJ, Ratswohl C, Zaborsky N, Rebhandl S, Schubert M, et al. TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia. Oncoimmunology. 2017;7:e1371399.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    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;121:1612–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Roessner PM, LLaó Cid L, Lupar E, Roider T, Bordas M, Schifflers C, et al. EOMES and IL-10 regulate anti-tumor activity of PD-1+ CD4+ T-cells in B-cell Non-Hodgkin lymphoma. 2020.

  11. 11.

    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;18:678–87.

    CAS  PubMed  Google Scholar 

  12. 12.

    Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. The. J Clin Investig. 2005;115:1797–805.

    PubMed  Google Scholar 

  13. 13.

    Rossmann ED, Lewin N, Jeddi-Tehrani M, Osterborg A, Mellstedt H. Intracellular T cell cytokines in patients with B cell chronic lymphocytic leukaemia (B-CLL). Eur J Haematol. 2002;68:299–306.

    CAS  PubMed  Google Scholar 

  14. 14.

    McClanahan F, Riches JC, Miller S, Day WP, Kotsiou E, Neuberg D, et al. Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Emicro-TCL1 CLL mouse model. Blood. 2015;126:212–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Buggins AGS, Patten PEM, Richards J, Thomas NSB, Mufti GJ, Devereux S. Tumor-derived IL-6 may contribute to the immunological defect in CLL. Leukemia. 2007;22:1084–7.

    PubMed  Google Scholar 

  16. 16.

    Podhorecka M, Dmoszynska A, Rolinski J, Wasik E. T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia-the three-color flow cytometry analysis. Leuk Res. 2002;26:657–60.

    CAS  PubMed  Google Scholar 

  17. 17.

    Roessner PM, Hanna BS, Ozturk S, Schulz R, Llao Cid L, Yazdanparast H, et al. TBET-expressing Th1 CD4(+) T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Emicro-TCL1 mice. British J. Haematol. 2020;189:133–45.

    CAS  Google Scholar 

  18. 18.

    Os A, Burgler S, Ribes AP, Funderud A, Wang D, Thompson KM, et al. Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells. Cell Rep. 2013;4:566–77.

    CAS  PubMed  Google Scholar 

  19. 19.

    Burgler S, Gimeno A, Parente-Ribes A, Wang D, Os A, Devereux S, et al. Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-gamma by a T-bet-dependent mechanism. J Immunol (Baltim, Md: 1950). 2015;194:827–35.

    Google Scholar 

  20. 20.

    Jain P, Javdan M, Feger FK, Chiu PY, Sison C, Damle RN, et al. Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance. Haematologica. 2012;97:599–607.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Hus I, Bojarska-Junak A, Chocholska S, Tomczak W, Wos J, Dmoszynska A, et al. Th17/IL-17A might play a protective role in chronic lymphocytic leukemia immunity. PloS One. 2013;8:e78091.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ahearne MJ, Willimott S, Pinon L, Kennedy DB, Miall F, Dyer MJ, et al. Enhancement of CD154/IL4 proliferation by the T follicular helper (Tfh) cytokine, IL21 and increased numbers of circulating cells resembling Tfh cells in chronic lymphocytic leukaemia. Br J Haematol. 2013;162:360–70.

    CAS  PubMed  Google Scholar 

  23. 23.

    Pascutti MF, Jak M, Tromp JM, Derks IA, Remmerswaal EB, Thijssen R, et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood. 2013;122:3010–9.

    CAS  PubMed  Google Scholar 

  24. 24.

    Cha Z, Zang Y, Guo H, Rechlic JR, Olasnova LM, Gu H, et al. Association of peripheral CD4+ CXCR5+ T cells with chronic lymphocytic leukemia. Tumour Biol: J Int Soc Oncodev Biol Med. 2013;34:3579–85.

    CAS  Google Scholar 

  25. 25.

    de Weerdt I, Hofland T, de Boer R, Dobber JA, Dubois J, van Nieuwenhuize D, et al. Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment. Blood Adv. 2019;3:2642–52.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Giannopoulos K, Schmitt M, Wlasiuk P, Chen J, Bojarska-Junak A, Kowal M, et al. The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide. Leukemia. 2008;22:222–4.

    CAS  PubMed  Google Scholar 

  27. 27.

    Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018–25.

    CAS  PubMed  Google Scholar 

  28. 28.

    Biancotto A, Dagur PK, Fuchs JC, Wiestner A, Bagwell CB, McCoy JP Jr. Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia. Mod Pathol. 2012;25:246–59.

    CAS  PubMed  Google Scholar 

  29. 29.

    D’Arena G, Laurenti L, Minervini MM, Deaglio S, Bonello L, De Martino L, et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk Res. 2011;35:363–8.

    PubMed  Google Scholar 

  30. 30.

    Weiss L, Melchardt T, Egle A, Grabmer C, Greil R, Tinhofer I. Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia. Cancer. 2011;117:2163–9.

    CAS  PubMed  Google Scholar 

  31. 31.

    D’Arena G, Simeon V, D’Auria F, Statuto T, Sanzo PD, Martino LD, et al. Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander? Am J Blood Res. 2013;3:52–7.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Hanna BS, Roessner PM, Scheffold A, Jebaraj BMC, Demerdash Y, Ozturk S, et al. PI3Kdelta inhibition modulates regulatory and effector T-cell differentiation and function in chronic lymphocytic leukemia. Leukemia. 2019;33:1427–38.

    CAS  PubMed  Google Scholar 

  33. 33.

    Piper KP, Karanth M, McLarnon A, Kalk E, Khan N, Murray J, et al. Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells. Clin Exp Immunol. 2011;166:154–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Lindqvist CA, Christiansson LH, Thorn I, Mangsbo S, Paul-Wetterberg G, Sundstrom C, et al. Both CD4+ FoxP3+ and CD4+ FoxP3- T cells from patients with B-cell malignancy express cytolytic markers and kill autologous leukaemic B cells in vitro. Immunology. 2011;133:296–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    D’Arena G, D’Auria F, Simeon V, Laurenti L, Deaglio S, Mansueto G, et al. A shorter time to the first treatment may be predicted by the absolute number of regulatory T-cells in patients with Rai stage 0 chronic lymphocytic leukemia. Am J Hematol. 2012;87:628–31.

    PubMed  Google Scholar 

  36. 36.

    Lad DP, Varma S, Varma N, Sachdeva MU, Bose P, Malhotra P. Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias. Leuk Lymphoma. 2013;54:1012–9.

    CAS  PubMed  Google Scholar 

  37. 37.

    Gorgun G, Ramsay AG, Holderried TA, Zahrieh D, Le Dieu R, Liu F, et al. E(mu)-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. Proc Natl Acad Sci USA. 2009;106:6250–5.

    CAS  PubMed  Google Scholar 

  38. 38.

    Wierz M, Pierson S, Guyonnet L, Viry E, Lequeux A, Oudin A, et al. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018;131:1617–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Wierz M, Janji B, Berchem G, Moussay E, Paggetti J. High-dimensional mass cytometry analysis revealed microenvironment complexity in chronic lymphocytic leukemia. Oncoimmunology. 2018;7:e1465167.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Motta M, Rassenti L, Shelvin BJ, Lerner S, Kipps TJ, Keating MJ, et al. Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia. 2005;19:1788–93.

    CAS  PubMed  Google Scholar 

  41. 41.

    Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–7.

    CAS  PubMed  Google Scholar 

  42. 42.

    Totterman TH, Carlsson M, Simonsson B, Bengtsson M, Nilsson K. T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease. Blood. 1989;74:786–92.

    CAS  PubMed  Google Scholar 

  43. 43.

    Christopoulos P, Pfeifer D, Bartholome K, Follo M, Timmer J, Fisch P, et al. Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood. 2011;117:3836–46.

    CAS  PubMed  Google Scholar 

  44. 44.

    Buschle M, Campana D, Carding SR, Richard C, Hoffbrand AV, Brenner MK. Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia. J Exp Med. 1993;177:213–8.

    CAS  PubMed  Google Scholar 

  45. 45.

    Bhattacharya N, Reichenzeller M, Caudron-Herger M, Haebe S, Brady N, Diener S, et al. Loss of cooperativity of secreted CD40L and increased dose-response to IL4 on CLL cell viability correlates with enhanced activation of NF-kB and STAT6. Int J Cancer. 2015;136:65–73.

    CAS  PubMed  Google Scholar 

  46. 46.

    Bagnara D, Kaufman MS, Calissano C, Marsilio S, Patten PE, Simone R, et al. A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease. Blood. 2011;117:5463–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Gauthier M, Durrieu F, Martin E, Peres M, Vergez F, Filleron T, et al. Prognostic role of CD4 T-cell depletion after frontline fludarabine, cyclophosphamide and rituximab in chronic lymphocytic leukaemia. BMC Cancer. 2019;19:809.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Kocher T, Asslaber D, Zaborsky N, Flenady S, Denk U, Reinthaler P, et al. CD4+ T cells, but not non-classical monocytes, are dispensable for the development of chronic lymphocytic leukemia in the TCL1-tg murine model. Leukemia. 2016;30:1409–13.

    CAS  PubMed  Google Scholar 

  49. 49.

    Hanna BS, Roessner PM, Yazdanparast H, Colomer D, Campo E, Kugler S, et al. Control of chronic lymphocytic leukemia development by clonally-expanded CD8(+) T-cells that undergo functional exhaustion in secondary lymphoid tissues. Leukemia. 2019;33:625–37.

    CAS  PubMed  Google Scholar 

  50. 50.

    Zhan YF, Brown LE, Deliyannis G, Seah S, Wijburg OL, Price J, et al. Responses against complex antigens in various models of CD4 T-cell deficiency - Surprises from an anti-CD4 antibody transgenic mouse. Immunologic Res. 2004;30:1–14.

    CAS  Google Scholar 

  51. 51.

    Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011;35:161–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Youngblood B, Hale JS, Kissick HT, Ahn E, Xu X, Wieland A, et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature. 2017;552:404–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Lopez JA, Susanto O, Jenkins MR, Lukoyanova N, Sutton VR, Law RH, et al. Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood. 2013;121:2659–68.

    CAS  PubMed  Google Scholar 

  54. 54.

    Hassin D, Garber OG, Meiraz A, Schiffenbauer YS, Berke G. Cytotoxic T lymphocyte perforin and Fas ligand working in concert even when Fas ligand lytic action is still not detectable. Immunology. 2011;133:190–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.

    CAS  PubMed  Google Scholar 

  56. 56.

    Schenkel JM, Masopust D. Tissue-resident memory T cells. Immunity. 2014;41:886–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

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

    CAS  PubMed  Google Scholar 

  58. 58.

    Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016;354:1160–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, et al. The epigenetic landscape of T cell exhaustion. Science. 2016;354:1165–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Kallies A, Zehn D, Utzschneider DT. Precursor exhausted T cells: key to successful immunotherapy? Nat Rev Immunol. 2020;20:128–36.

    CAS  PubMed  Google Scholar 

  61. 61.

    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;443:350–4.

    CAS  PubMed  Google Scholar 

  62. 62.

    Zhang Y, Huang S, Gong D, Qin Y, Shen Q. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol. 2010;7:389–95.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    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. The. J Exp Med. 2010;207:2175–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Catovsky D, Miliani E, Okos A, Galton DA. Clinical significance of T-cells in chronic lymphocytic leukaemia. Lancet (Lond, Engl). 1974;2:751–2.

    CAS  Google Scholar 

  65. 65.

    Mills KH, Cawley JC. Suppressor T cells in B-cell chronic lymphocytic leukaemia: relationship to clinical stage. Leuk Res. 1982;6:653–7.

    CAS  PubMed  Google Scholar 

  66. 66.

    Herrmann F, Lochner A, Philippen H, Jauer B, Ruhl H. Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell type. Clin Exp Immunol. 1982;49:157–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Platsoucas CD, Galinski M, Kempin S, Reich L, Clarkson B, Good RA. Abnormal T lymphocyte subpopulations in patients with B cell chronic lymphocytic leukemia: an analysis by monoclonal antibodies. J Immunol (Baltim, Md: 1950). 1982;129:2305–12.

    CAS  Google Scholar 

  68. 68.

    Porakishvili N, Roschupkina T, Kalber T, Jewell AP, Patterson K, Yong K, et al. Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL). Clin Exp Immunol. 2001;126:29–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Peller S, Kaufman S. Decreased CD45RA T cells in B-cell chronic lymphatic leukemia patients: correlation with disease stage. Blood. 1991;78:1569–73.

    CAS  PubMed  Google Scholar 

  70. 70.

    Tonino SH, van de Berg PJ, Yong SL, ten Berge IJ, Kersten MJ, van Lier RA, et al. Expansion of effector T cells associated with decreased PD-1 expression in patients with indolent B cell lymphomas and chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:1785–94.

    CAS  PubMed  Google Scholar 

  71. 71.

    Wu J, Xu X, Lee EJ, Shull AY, Pei L, Awan F, et al. Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming. Oncotarget. 2016;7:40558–70.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Gonzalez-Rodriguez AP, Contesti J, Huergo-Zapico L, Lopez-Soto A, Fernandez-Guizan A, Acebes-Huerta A, et al. Prognostic significance of CD8 and CD4 T cells in chronic lymphocytic leukemia. Leuk Lymphoma. 2010;51:1829–36.

    CAS  PubMed  Google Scholar 

  73. 73.

    Mackus WJ, Frakking FN, Grummels A, Gamadia LE, De Bree GJ, Hamann D, et al. Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia. Blood. 2003;102:1057–63.

    CAS  PubMed  Google Scholar 

  74. 74.

    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;98:953–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Gothert JR, Eisele L, Klein-Hitpass L, Weber S, Zesewitz ML, Sellmann L, et al. Expanded CD8+ T cells of murine and human CLL are driven into a senescent KLRG1+ effector memory phenotype. Cancer Immunol, Immunotherapy: CII. 2013;62:1697–709.

    Google Scholar 

  76. 76.

    Gonnord P, Costa M, Abreu A, Peres M, Ysebaert L, Gadat S, et al. Multiparametric analysis of CD8(+) T cell compartment phenotype in chronic lymphocytic leukemia reveals a signature associated with progression toward therapy. Oncoimmunology. 2019;8:e1570774.

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Novak M, Prochazka V, Turcsanyi P, Papajik T. Numbers of CD8+PD-1+ and CD4+PD-1+ cells in peripheral blood of patients with chronic lymphocytic leukemia are independent of binet stage and are significantly higher compared to healthy volunteers. Acta Haematologica. 2015;134:208–14.

    CAS  PubMed  Google Scholar 

  78. 78.

    Taghiloo S, Allahmoradi E, Tehrani M, Hossein-Nataj H, Shekarriz R, Janbabaei G, et al. Frequency and functional characterization of exhausted CD8(+) T cells in chronic lymphocytic leukemia. Eur J Haematol. 2017;98:622–31.

    CAS  PubMed  Google Scholar 

  79. 79.

    Hofbauer JP, Heyder C, Denk U, Kocher T, Holler C, Trapin D, et al. Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. Leukemia. 2011;25:1452–8.

    PubMed  Google Scholar 

  80. 80.

    Llao Cid L, Hanna BS, Iskar M, Roessner PM, Ozturk S, Lichter P, et al. CD8(+) T-cells of CLL-bearing mice acquire a transcriptional program of T-cell activation and exhaustion. Leuk Lymphoma. 2020;61:351–6.

    CAS  PubMed  Google Scholar 

  81. 81.

    Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Investig. 2008;118:2427–37.

    CAS  PubMed  Google Scholar 

  82. 82.

    Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;120:1412–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Vardi A, Vlachonikola E, Karypidou M, Stalika E, Bikos V, Gemenetzi K, et al. Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements. Leukemia. 2017;31:1555–61.

    CAS  PubMed  Google Scholar 

  84. 84.

    Blanco G, Vardi A, Puiggros A, Gomez-Llonin A, Muro M, Rodriguez-Rivera M, et al. Restricted T cell receptor repertoire in CLL-like monoclonal B cell lymphocytosis and early stage CLL. Oncoimmunology. 2018;7:e1432328.

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Serrano D, Monteiro J, Allen SL, Kolitz J, Schulman P, Lichtman SM, et al. Clonal expansion within the CD4+CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia. J Immunol (Baltim, Md: 1950). 1997;158:1482–9.

    CAS  Google Scholar 

  86. 86.

    Kowalewski DJ, Schuster H, Backert L, Berlin C, Kahn S, Kanz L, et al. HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL). Proc Natl Acad Sci USA. 2015;112:E166–75.

    CAS  PubMed  Google Scholar 

  87. 87.

    Asslaber D, Qi Y, Maeding N, Steiner M, Denk U, Hopner JP, et al. B-cell-specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion. Blood. 2019;134:1717–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015;126:2686–94.

    PubMed  PubMed Central  Google Scholar 

  90. 90.

    Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017;18:297–311.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl J Med. 2014;370:997–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56:2779–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Pleyer C, Wiestner A, Sun C. Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia. Leuk Lymphoma. 2018;59:2792–800.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3:317–30.

    CAS  PubMed  Google Scholar 

  96. 96.

    Dong S, Harrington BK, Hu EY, Greene JT, Lehman AM, Tran M, et al. PI3K p110delta inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression. J Clin Investig. 2019;129:122–36.

    PubMed  Google Scholar 

  97. 97.

    Chellappa S, Kushekhar K, Munthe LA, Tjonnfjord GE, Aandahl EM, Okkenhaug K, et al. The PI3K p110delta isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function. J Immunol (Baltim, Md: 1950). 2019;202:1397–405.

    CAS  Google Scholar 

  98. 98.

    Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510:407–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122:2539–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Mhibik M, Wiestner A, Sun C. Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL. Int J Mol Sci. 2019;21.

  101. 101.

    Yin Q, Sivina M, Robins H, Yusko E, Vignali M, O’Brien S, et al. Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia. J Immunol (Baltim, Md: 1950). 2017;198:1740–7.

    CAS  Google Scholar 

  102. 102.

    Niemann CU, Herman SE, Maric I, Gomez-Rodriguez J, Biancotto A, Chang BY, et al. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib-findings from an investigator-initiated phase II study. Clin Cancer Res. 2016;22:1572–82.

    CAS  PubMed  Google Scholar 

  103. 103.

    Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. The. J Clin Investig. 2017;127:3052–64.

    PubMed  Google Scholar 

  104. 104.

    Hofland T, de Weerdt I, Ter Burg H, de Boer R, Tannheimer S, Tonino SH, et al. Dissection of the effects of JAK and BTK inhibitors on the functionality of healthy and malignant lymphocytes. J Immunol (Baltim, Md: 1950). 2019;203:2100–9.

    CAS  Google Scholar 

  105. 105.

    Hanna BS, Yazdanparast H, Demerdash Y, Roessner PM, Schulz R, Lichter P, et al. Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice. Haematologica. 2020.

  106. 106.

    Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127:1117–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Podhorecka M, Goracy A, Szymczyk A, Kowal M, Ibanez B, Jankowska-Lecka O, et al. Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number. Oncotarget 2017;8:34661–9.

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Kondo K, Shaim H, Thompson PA, Burger JA, Keating M, Estrov Z, et al. Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia. 2018;32:960–70.

    CAS  PubMed  Google Scholar 

  109. 109.

    Cubillos-Zapata C, Avendano-Ortiz J, Cordoba R, Hernandez-Jimenez E, Toledano V, Perez de Diego R, et al. Ibrutinib as an antitumor immunomodulator in patients with refractory chronic lymphocytic leukemia. Oncoimmunology. 2016;5:e1242544.

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    McClanahan F, Hanna B, Miller S, Clear AJ, Lichter P, Gribben JG, et al. PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood. 2015;126:203–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129:3419–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Younes A, Brody J, Carpio C, Lopez-Guillermo A, Ben-Yehuda D, Ferhanoglu B, et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Lancet Haematol. 2019;6:e67–e78.

    PubMed  Google Scholar 

  113. 113.

    Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139.

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Turtle CJ, Hay KA, Hanafi LA, Li D, Cherian S, Chen X, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol: Off J Am Soc Clin Oncol. 2017;35:3010–20.

    CAS  Google Scholar 

  115. 115.

    Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382:545–53.

    CAS  PubMed  Google Scholar 

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The authors would like to thank Dr. Selcen Öztürk, Laura Llaó Cid, and Dr. Emma Philipps for their critical revision of the manuscript. Graphs were created with

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PMR and MS reviewed the literature, prepared the figures, wrote, and revised the manuscript.

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Correspondence to Martina Seiffert.

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Roessner, P.M., Seiffert, M. T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease?. Leukemia 34, 2012–2024 (2020).

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