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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Youhan Liu, Wen Ma, Xuewen Tian, Qinglu Wang, Xin Lu, Ying Luo* and Jun Xu*

DOI: 10.2174/0118715206321574240821112747

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Immunomodulatory Roles of IL-15 in Immune Cells and its Potential for Cancer Immunotherapy

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Abstract

Interleukin-15 (IL-15) was identified in 1994 as a T-cell growth factor with the capability to mimic the functions of IL-2. IL-15 engages with the IL-15Rα subunit expressed on the surface of antigen-presenting cells (APCs) and, through a trans-presentation mechanism, activates the IL-2/IL-15Rβγ complex receptor on the surface of natural killer (NK) cells and CD8+ T cells. This interaction initiates a cascade of downstream signaling pathways, playing a pivotal role in the activation, proliferation, and anti-apoptotic processes in NK cells, CD8+ T cells, and B cells. It provides a substantial theoretical foundation and potential therapeutic targets for tumor immunotherapy. Whether through active or passive immunotherapeutic strategies, IL-15 has emerged as a critical molecule for stimulating anti-tumor cell proliferation.

Keywords: Tumor, NK, CD8+T, B cell, IL-15, natural killer.

Graphical Abstract

[1]
Liu, Z.; Han, C.; Fu, Y.X. Targeting innate sensing in the tumor microenvironment to improve immunotherapy. Cell. Mol. Immunol., 2020, 17(1), 13-26.
[http://dx.doi.org/10.1038/s41423-019-0341-y] [PMID: 31844141]
[2]
Takatsu, K.; Nakajima, H. IL-5 and eosinophilia. Curr. Opin. Immunol., 2008, 20(3), 288-294.
[http://dx.doi.org/10.1016/j.coi.2008.04.001] [PMID: 18511250]
[3]
Weng, N.P.; Liu, K.; Catalfamo, M.; Li, Y.; Henkart, P.A. IL-15 is a growth factor and an activator of CD8 memory T cells. Ann. N. Y. Acad. Sci., 2002, 975(1), 46-56.
[http://dx.doi.org/10.1111/j.1749-6632.2002.tb05940.x] [PMID: 12538153]
[4]
Giri, J.G.; Anderson, D.M.; Kumaki, S.; Park, L.S.; Grabstein, K.H.; Cosman, D. IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J. Leukoc. Biol., 1995, 57(5), 763-766.
[http://dx.doi.org/10.1002/jlb.57.5.763] [PMID: 7759955]
[5]
Fehniger, T.A. Mystery solved: IL-15. J. Immunol., 2019, 202(11), 3125-3126.
[http://dx.doi.org/10.4049/jimmunol.1900419] [PMID: 31109944]
[6]
Yang, Y.; Lundqvist, A. Immunomodulatory effects of IL-2 and IL-15; implications for cancer immunotherapy. Cancers (Basel), 2020, 12(12), 3586.
[http://dx.doi.org/10.3390/cancers12123586] [PMID: 33266177]
[7]
Bilotta, M.T.; Antignani, A.; Fitzgerald, D.J. Managing the TME to improve the efficacy of cancer therapy. Front. Immunol., 2022, 13, 954992.
[http://dx.doi.org/10.3389/fimmu.2022.954992] [PMID: 36341428]
[8]
Becker, J.C.; Andersen, M.H.; Schrama, D.; thor Straten, P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother., 2013, 62(7), 1137-1148.
[http://dx.doi.org/10.1007/s00262-013-1434-6] [PMID: 23666510]
[9]
Hanahan, D.; Coussens, L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell, 2012, 21(3), 309-322.
[http://dx.doi.org/10.1016/j.ccr.2012.02.022] [PMID: 22439926]
[10]
Mannino, M.H.; Zhu, Z.; Xiao, H.; Bai, Q.; Wakefield, M.R.; Fang, Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett., 2015, 367(2), 103-107.
[http://dx.doi.org/10.1016/j.canlet.2015.07.009] [PMID: 26188281]
[11]
Larson, C.; Oronsky, B.; Carter, C.A.; Oronsky, A.; Knox, S.J.; Sher, D.; Reid, T.R. TGF-beta: a master immune regulator. Expert Opin. Ther. Targets, 2020, 24(5), 427-438.
[http://dx.doi.org/10.1080/14728222.2020.1744568] [PMID: 32228232]
[12]
Vaupel, P.; Multhoff, G. Accomplices of the hypoxic tumor microenvironment compromising antitumor immunity: Adenosine, lactate, acidosis, vascular endothelial growth factor, potassium ions, and phosphatidylserine. Front. Immunol., 2017, 8, 1887.
[http://dx.doi.org/10.3389/fimmu.2017.01887] [PMID: 29312351]
[13]
Madden, M.Z.; Rathmell, J.C. The complex integration of T-cell metabolism and immunotherapy. Cancer Discov., 2021, 11(7), 1636-1643.
[http://dx.doi.org/10.1158/2159-8290.CD-20-0569] [PMID: 33795235]
[14]
Yan, J.; Smyth, M.J.; Teng, M.W.L. Interleukin (IL)-12 and IL-23 and their conflicting roles in cancer. Cold Spring Harb. Perspect. Biol., 2018, 10(7), a028530.
[http://dx.doi.org/10.1101/cshperspect.a028530] [PMID: 28716888]
[15]
Takaki, S.; Kanazawa, H.; Shiiba, M.; Takatsu, K. A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. Mol. Cell. Biol., 1994, 14(11), 7404-7413.
[http://dx.doi.org/10.1128/MCB.14.11.7404] [PMID: 7935454]
[16]
Mlecnik, B.; Bindea, G.; Angell, H.K.; Sasso, M.S.; Obenauf, A.C.; Fredriksen, T.; Lafontaine, L.; Bilocq, A.M.; Kirilovsky, A.; Tosolini, M.; Waldner, M.; Berger, A.; Fridman, W.H.; Rafii, A.; Valge-Archer, V.; Pagès, F.; Speicher, M.R.; Galon, J. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci. Transl. Med., 2014, 6(228), 228ra37.
[http://dx.doi.org/10.1126/scitranslmed.3007240] [PMID: 24648340]
[17]
‘Mac’ Cheever, M.A. Twelve immunotherapy drugs that could cure cancers. Immunol. Rev., 2008, 222(1), 357-368.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00604.x] [PMID: 18364014]
[18]
Giri, J.G.; Kumaki, S.; Ahdieh, M.; Friend, D.J.; Loomis, A.; Shanebeck, K.; DuBose, R.; Cosman, D.; Park, L.S.; Anderson, D.M. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J., 1995, 14(15), 3654-3663.
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb00035.x] [PMID: 7641685]
[19]
Badoual, C.; Bouchaud, G.; Agueznay, N.E.H.; Mortier, E.; Hans, S.; Gey, A.; Fernani, F.; Peyrard, S.; -Puig, P.L.; Bruneval, P.; Sastre, X.; Plet, A.; Garrigue-Antar, L.; Quintin-Colonna, F.; Fridman, W.H.; Brasnu, D.; Jacques, Y.; Tartour, E. The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res., 2008, 68(10), 3907-3914.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6842] [PMID: 18483276]
[20]
Zhang, N.; Bevan, M.J. CD8(+) T cells: foot soldiers of the immune system. Immunity, 2011, 35(2), 161-168.
[http://dx.doi.org/10.1016/j.immuni.2011.07.010] [PMID: 21867926]
[21]
Reiser, J.; Banerjee, A. Effector, memory, and dysfunctional CD8 + T cell fates in the antitumor immune response. J. Immunol. Res., 2016, 2016, 1-14.
[http://dx.doi.org/10.1155/2016/8941260] [PMID: 27314056]
[22]
Klebanoff, C.A.; Gattinoni, L.; Palmer, D.C.; Muranski, P.; Ji, Y.; Hinrichs, C.S.; Borman, Z.A.; Kerkar, S.P.; Scott, C.D.; Finkelstein, S.E.; Rosenberg, S.A.; Restifo, N.P. Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin. Cancer Res., 2011, 17(16), 5343-5352.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0503] [PMID: 21737507]
[23]
Gao, S.; Liang, X.; Wang, H.; Bao, B.; Zhang, K.; Zhu, Y.; Shao, Q. Stem cell-like memory T cells: A perspective from the dark side. Cell. Immunol., 2021, 361, 104273.
[http://dx.doi.org/10.1016/j.cellimm.2020.104273] [PMID: 33422699]
[24]
Germain, R.N. T-cell development and the CD4–CD8 lineage decision. Nat. Rev. Immunol., 2002, 2(5), 309-322.
[http://dx.doi.org/10.1038/nri798] [PMID: 12033737]
[25]
Lu, C.; Liu, Y.; Ali, N.M.; Zhang, B.; Cui, X. The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front. Immunol., 2023, 13, 1039260.
[http://dx.doi.org/10.3389/fimmu.2022.1039260] [PMID: 36741415]
[26]
Kucuksezer, U.C.; Aktas Cetin, E.; Esen, F.; Tahrali, I.; Akdeniz, N.; Gelmez, M.Y.; Deniz, G. The role of natural killer cells in autoimmune diseases. Front. Immunol., 2021, 12, 622306.
[http://dx.doi.org/10.3389/fimmu.2021.622306] [PMID: 33717125]
[27]
Nolz, J.C.; Richer, M.J. Control of memory CD8+ T cell longevity and effector functions by IL-15. Mol. Immunol., 2020, 117, 180-188.
[http://dx.doi.org/10.1016/j.molimm.2019.11.011] [PMID: 31816491]
[28]
Blank, C.U.; Haining, W.N.; Held, W.; Hogan, P.G.; Kallies, A.; Lugli, E.; Lynn, R.C.; Philip, M.; Rao, A.; Restifo, N.P.; Schietinger, A.; Schumacher, T.N.; Schwartzberg, P.L.; Sharpe, A.H.; Speiser, D.E.; Wherry, E.J.; Youngblood, B.A.; Zehn, D. Defining ‘T cell exhaustion’. Nat. Rev. Immunol., 2019, 19(11), 665-674.
[http://dx.doi.org/10.1038/s41577-019-0221-9] [PMID: 31570879]
[29]
Lee, J.; Lee, K.; Bae, H.; Lee, K.; Lee, S.; Ma, J.; Jo, K.; Kim, I.; Jee, B.; Kang, M.; Im, S.J. IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation. Front. Immunol., 2023, 14, 1117092.
[http://dx.doi.org/10.3389/fimmu.2023.1117092] [PMID: 37409128]
[30]
O’Sullivan, D.; van der Windt, G.J.W.; Huang, S.C.C.; Curtis, J.D.; Chang, C.H.; Buck, M.D.; Qiu, J.; Smith, A.M.; Lam, W.Y.; DiPlato, L.M.; Hsu, F.F.; Birnbaum, M.J.; Pearce, E.J.; Pearce, E.L. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity, 2018, 49(2), 375-376.
[http://dx.doi.org/10.1016/j.immuni.2018.07.018] [PMID: 30134202]
[31]
Kurtulus, S.; Tripathi, P.; Moreno-Fernandez, M.E.; Sholl, A.; Katz, J.D.; Grimes, H.L.; Hildeman, D.A. Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim. J. Immunol., 2011, 186(10), 5729-5737.
[http://dx.doi.org/10.4049/jimmunol.1100102] [PMID: 21451108]
[32]
Waldmann, T.A.; Miljkovic, M.D.; Conlon, K.C. Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer. J. Exp. Med., 2020, 217(1), e20191062.
[http://dx.doi.org/10.1084/jem.20191062] [PMID: 31821442]
[33]
Goldrath, A.W.; Sivakumar, P.V.; Glaccum, M.; Kennedy, M.K.; Bevan, M.J.; Benoist, C.; Mathis, D.; Butz, E.A. Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med., 2002, 195(12), 1515-1522.
[http://dx.doi.org/10.1084/jem.20020033] [PMID: 12070279]
[34]
Schluns, K.S.; Williams, K.; Ma, A.; Zheng, X.X.; Lefrançois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol., 2002, 168(10), 4827-4831.
[http://dx.doi.org/10.4049/jimmunol.168.10.4827] [PMID: 11994430]
[35]
Tan, J.T.; Ernst, B.; Kieper, W.C.; LeRoy, E.; Sprent, J.; Surh, C.D. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med., 2002, 195(12), 1523-1532.
[http://dx.doi.org/10.1084/jem.20020066] [PMID: 12070280]
[36]
Kurz, E.; Hirsch, C.A.; Dalton, T.; Shadaloey, S.A.; Khodadadi-Jamayran, A.; Miller, G.; Pareek, S.; Rajaei, H.; Mohindroo, C.; Baydogan, S.; Ngo-Huang, A.; Parker, N.; Katz, M.H.G.; Petzel, M.; Vucic, E.; McAllister, F.; Schadler, K.; Winograd, R.; Bar-Sagi, D. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell, 2022, 40(7), 720-737.e5.
[http://dx.doi.org/10.1016/j.ccell.2022.05.006] [PMID: 35660135]
[37]
Ali, A.K.; Nandagopal, N.; Lee, S.H. IL-15–PI3K–AKT–mTOR: A critical pathway in the life journey of natural killer cells. Front. Immunol., 2015, 6, 355.
[http://dx.doi.org/10.3389/fimmu.2015.00355] [PMID: 26257729]
[38]
Cheuk, S.; Schlums, H.; Gallais Sérézal, I.; Martini, E.; Chiang, S.C.; Marquardt, N.; Gibbs, A.; Detlofsson, E.; Introini, A.; Forkel, M.; Höög, C.; Tjernlund, A.; Michaëlsson, J.; Folkersen, L.; Mjösberg, J.; Blomqvist, L.; Ehrström, M.; Ståhle, M.; Bryceson, Y.T.; Eidsmo, L. CD49a expression defines tissue-resident CD8+ T cells poised for cytotoxic function in human skin. Immunity, 2017, 46(2), 287-300.
[http://dx.doi.org/10.1016/j.immuni.2017.01.009] [PMID: 28214226]
[39]
Zhou, X.; Yu, J.; Cheng, X.; Zhao, B.; Manyam, G.C.; Zhang, L.; Schluns, K.; Li, P.; Wang, J.; Sun, S.C. The deubiquitinase Otub1 controls the activation of CD8+ T cells and NK cells by regulating IL-15-mediated priming. Nat. Immunol., 2019, 20(7), 879-889.
[http://dx.doi.org/10.1038/s41590-019-0405-2] [PMID: 31182807]
[40]
Raulet, D.H.; Vance, R.E. Self-tolerance of natural killer cells. Nat. Rev. Immunol., 2006, 6(7), 520-531.
[http://dx.doi.org/10.1038/nri1863] [PMID: 16799471]
[41]
Soelistyoningsih, D.; Susianti, H.; Kalim, H.; Handono, K. The phenotype of CD3–CD56bright and CD3–CD56dim natural killer cells in systemic lupus erythematosus patients and its relation to disease activity. Reumatologia, 2022, 60(4), 258-265.
[http://dx.doi.org/10.5114/reum.2022.119042] [PMID: 36186836]
[42]
Poznanski, S.M.; Ashkar, A.A. Shining light on the significance of NK cell CD56 brightness. Cell. Mol. Immunol., 2018, 15(12), 1071-1073.
[http://dx.doi.org/10.1038/s41423-018-0163-3] [PMID: 30275534]
[43]
Michel, T.; Poli, A.; Cuapio, A.; Briquemont, B.; Iserentant, G.; Ollert, M.; Zimmer, J. Human CD56 bright NK cells: An update. J. Immunol., 2016, 196(7), 2923-2931.
[http://dx.doi.org/10.4049/jimmunol.1502570] [PMID: 26994304]
[44]
Koch, J.; Steinle, A.; Watzl, C.; Mandelboim, O. Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol., 2013, 34(4), 182-191.
[http://dx.doi.org/10.1016/j.it.2013.01.003] [PMID: 23414611]
[45]
Terrén, I.; Orrantia, A.; Vitallé, J.; Astarloa-Pando, G.; Zenarruzabeitia, O.; Borrego, F. Modulating NK cell metabolism for cancer immunotherapy. Semin. Hematol., 2020, 57(4), 213-224.
[http://dx.doi.org/10.1053/j.seminhematol.2020.10.003] [PMID: 33256914]
[46]
Correia, A.L.; Guimaraes, J.C.; Auf der Maur, P.; De Silva, D.; Trefny, M.P.; Okamoto, R.; Bruno, S.; Schmidt, A.; Mertz, K.; Volkmann, K.; Terracciano, L.; Zippelius, A.; Vetter, M.; Kurzeder, C.; Weber, W.P.; Bentires-Alj, M. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature, 2021, 594(7864), 566-571.
[http://dx.doi.org/10.1038/s41586-021-03614-z] [PMID: 34079127]
[47]
Castillo, E.F.; Schluns, K.S. Regulating the immune system via IL-15 transpresentation. Cytokine, 2012, 59(3), 479-490.
[http://dx.doi.org/10.1016/j.cyto.2012.06.017] [PMID: 22795955]
[48]
Balsamo, M.; Scordamaglia, F.; Pietra, G.; Manzini, C.; Cantoni, C.; Boitano, M.; Queirolo, P.; Vermi, W.; Facchetti, F.; Moretta, A.; Moretta, L.; Mingari, M.C.; Vitale, M. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc. Natl. Acad. Sci. USA, 2009, 106(49), 20847-20852.
[http://dx.doi.org/10.1073/pnas.0906481106] [PMID: 19934056]
[49]
Ma, S.; Caligiuri, M.A.; Yu, J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol., 2022, 43(10), 833-847.
[http://dx.doi.org/10.1016/j.it.2022.08.004] [PMID: 36058806]
[50]
Dean, I.; Lee, C.Y.C.; Tuong, Z.K.; Li, Z.; Tibbitt, C.A.; Willis, C.; Gaspal, F.; Kennedy, B.C.; Matei-Rascu, V.; Fiancette, R.; Nordenvall, C.; Lindforss, U.; Baker, S.M.; Stockmann, C.; Sexl, V.; Hammond, S.A.; Dovedi, S.J.; Mjösberg, J.; Hepworth, M.R.; Carlesso, G.; Clatworthy, M.R.; Withers, D.R. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat. Commun., 2024, 15(1), 683.
[http://dx.doi.org/10.1038/s41467-024-44789-z] [PMID: 38267402]
[51]
Mishra, H.K.; Dixon, K.J.; Pore, N.; Felices, M.; Miller, J.S.; Walcheck, B. Activation of ADAM17 by IL-15 limits human NK cell proliferation. Front. Immunol., 2021, 12, 711621.
[http://dx.doi.org/10.3389/fimmu.2021.711621] [PMID: 34367174]
[52]
Watkinson, F.; Nayar, S.K.; Rani, A.; Sakellariou, C.A.; Elhage, O.; Papaevangelou, E.; Dasgupta, P.; Galustian, C. IL-15 upregulates telomerase expression and potently increases proliferative capacity of NK, NKT-like, and CD8 T cells. Front. Immunol., 2021, 11, 594620.
[http://dx.doi.org/10.3389/fimmu.2020.594620] [PMID: 33537030]
[53]
Ghosh, A.K.; Sinha, D.; Biswas, R.; Biswas, T. IL-15 stimulates NKG2D while promoting IgM expression of B-1a cells. Cytokine, 2017, 95, 43-50.
[http://dx.doi.org/10.1016/j.cyto.2017.02.014] [PMID: 28235675]
[54]
Zhang, C.; Zhang, J.; Niu, J.; Zhang, J.; Tian, Z. Interleukin-15 improves cytotoxicity of natural killer cells via up-regulating NKG2D and cytotoxic effector molecule expression as well as STAT1 and ERK1/2 phosphorylation. Cytokine, 2008, 42(1), 128-136.
[http://dx.doi.org/10.1016/j.cyto.2008.01.003] [PMID: 18280748]
[55]
Khameneh, H.J.; Fonta, N.; Zenobi, A.; Niogret, C.; Ventura, P.; Guerra, C.; Kwee, I.; Rinaldi, A.; Pecoraro, M.; Geiger, R.; Cavalli, A.; Bertoni, F.; Vivier, E.; Trumpp, A.; Guarda, G. Myc controls NK cell development, IL-15-driven expansion, and translational machinery. Life Sci. Alliance, 2023, 6(7), e202302069.
[http://dx.doi.org/10.26508/lsa.202302069] [PMID: 37105715]
[56]
Wang, X.; Zhao, X.Y. Transcription factors associated with IL-15 cytokine signaling during NK cell development. Front. Immunol., 2021, 12, 610789.
[http://dx.doi.org/10.3389/fimmu.2021.610789] [PMID: 33815365]
[57]
Carson, W.E.; Fehniger, T.A.; Haldar, S.; Eckhert, K.; Lindemann, M.J.; Lai, C.F.; Croce, C.M.; Baumann, H.; Caligiuri, M.A. A potential role for interleukin-15 in the regulation of human natural killer cell survival. J. Clin. Invest., 1997, 99(5), 937-943.
[http://dx.doi.org/10.1172/JCI119258] [PMID: 9062351]
[58]
Huntington, N.D.; Puthalakath, H.; Gunn, P.; Naik, E.; Michalak, E.M.; Smyth, M.J.; Tabarias, H.; Degli-Esposti, M.A.; Dewson, G.; Willis, S.N.; Motoyama, N.; Huang, D.C.S.; Nutt, S.L.; Tarlinton, D.M.; Strasser, A. Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat. Immunol., 2007, 8(8), 856-863.
[http://dx.doi.org/10.1038/ni1487] [PMID: 17618288]
[59]
Koka, R.; Burkett, P.R.; Chien, M.; Chai, S.; Chan, F.; Lodolce, J.P.; Boone, D.L.; Ma, A. Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice. J. Exp. Med., 2003, 197(8), 977-984.
[http://dx.doi.org/10.1084/jem.20021836] [PMID: 12695489]
[60]
Oberoi, P.; Kamenjarin, K.; Villena Ossa, J.F.; Uherek, B.; Bönig, H.; Wels, W.S. Directed differentiation of mobilized hematopoietic stem and progenitor cells into functional NK cells with enhanced antitumor activity. Cells, 2020, 9(4), 811.
[http://dx.doi.org/10.3390/cells9040811] [PMID: 32230942]
[61]
Wang, Y.; Zhang, Y.; Yi, P.; Dong, W.; Nalin, A.P.; Zhang, J.; Zhu, Z.; Chen, L.; Benson, D.M.; Mundy-Bosse, B.L.; Freud, A.G.; Caligiuri, M.A.; Yu, J. The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells. Nat. Immunol., 2019, 20(1), 10-17.
[http://dx.doi.org/10.1038/s41590-018-0265-1] [PMID: 30538328]
[62]
Ma, S.; Han, J.; Li, Z.; Xiao, S.; Zhang, J.; Yan, J.; Tang, T.; Barr, T.; Kraft, A.S.; Caligiuri, M.A.; Yu, J. An XBP1s–PIM-2 positive feedback loop controls IL-15–mediated survival of natural killer cells. Sci. Immunol., 2023, 8(81), eabn7993.
[http://dx.doi.org/10.1126/sciimmunol.abn7993] [PMID: 36897958]
[63]
Roy, K.; Chakraborty, M.; Kumar, A.; Manna, A.K.; Roy, N.S. The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells. Front. Immunol., 2023, 14, 1185597.
[http://dx.doi.org/10.3389/fimmu.2023.1185597] [PMID: 38169968]
[64]
Cargill, T.; Culver, E.L. The role of B cells and B cell therapies in immune-mediated liver diseases. Front. Immunol., 2021, 12, 661196.
[http://dx.doi.org/10.3389/fimmu.2021.661196] [PMID: 33936097]
[65]
Wang, Y.; Liu, J.; Burrows, P.D.; Wang, J.Y. B cell development and maturation. Adv. Exp. Med. Biol., 2020, 1254, 1-22.
[http://dx.doi.org/10.1007/978-981-15-3532-1_1] [PMID: 32323265]
[66]
Yoshimoto, M. The ontogeny of murine B-1a cells. Int. J. Hematol., 2020, 111(5), 622-627.
[http://dx.doi.org/10.1007/s12185-019-02787-8] [PMID: 31802412]
[67]
Sabatino, J.J., Jr; Pröbstel, A.K.; Zamvil, S.S. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat. Rev. Neurosci., 2019, 20(12), 728-745.
[http://dx.doi.org/10.1038/s41583-019-0233-2] [PMID: 31712781]
[68]
Anderson, N.M.; Simon, M.C. The tumor microenvironment. Curr. Biol., 2020, 30(16), R921-R925.
[http://dx.doi.org/10.1016/j.cub.2020.06.081] [PMID: 32810447]
[69]
Chandnani, N.; Gupta, I.; Mandal, A.; Sarkar, K. Participation of B cell in immunotherapy of cancer. Pathol. Res. Pract., 2024, 255, 155169.
[http://dx.doi.org/10.1016/j.prp.2024.155169] [PMID: 38330617]
[70]
Rastogi, I.; Jeon, D.; Moseman, J.E.; Muralidhar, A.; Potluri, H.K.; McNeel, D.G. Role of B cells as antigen presenting cells. Front. Immunol., 2022, 13, 954936.
[http://dx.doi.org/10.3389/fimmu.2022.954936] [PMID: 36159874]
[71]
Laumont, C.M.; Nelson, B.H. B cells in the tumor microenvironment: Multi-faceted organizers, regulators, and effectors of anti-tumor immunity. Cancer Cell, 2023, 41(3), 466-489.
[http://dx.doi.org/10.1016/j.ccell.2023.02.017] [PMID: 36917951]
[72]
Armitage, R.J.; Macduff, B.M.; Eisenman, J.; Paxton, R.; Grabstein, K.H. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J. Immunol., 1995, 154(2), 483-490.
[http://dx.doi.org/10.4049/jimmunol.154.2.483] [PMID: 7814861]
[73]
Kanti Ghosh, A.; Sinha, D.; Mukherjee, S.; Biswas, R.; Biswas, T. IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression. Cell. Mol. Immunol., 2016, 13(2), 229-239.
[http://dx.doi.org/10.1038/cmi.2015.08] [PMID: 25748019]
[74]
Gill, N.; Paltser, G.; Ashkar, A.A. Interleukin-15 expression affects homeostasis and function of B cells through NK cell-derived interferon-γ. Cell. Immunol., 2009, 258(1), 59-64.
[http://dx.doi.org/10.1016/j.cellimm.2009.03.010] [PMID: 19361783]
[75]
Waldmann, T.; Dubois, S.; Tagaya, Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity, 2001, 14(2), 105-110.
[http://dx.doi.org/10.1016/S1074-7613(09)00091-0] [PMID: 11239443]
[76]
Nagy, É.; Mocsár, G.; Sebestyén, V.; Volkó, J.; Papp, F.; Tóth, K.; Damjanovich, S.; Panyi, G.; Waldmann, T.A.; Bodnár, A.; Vámosi, G. Membrane Potential Distinctly Modulates Mobility and Signaling of IL-2 and IL-15 Receptors in T Cells. Biophys. J., 2018, 114(10), 2473-2482.
[http://dx.doi.org/10.1016/j.bpj.2018.04.038] [PMID: 29754714]
[77]
Hilton, L.R.; Rätsep, M.T.; VandenBroek, M.M.; Jafri, S.; Laverty, K.J.; Mitchell, M.; Theilmann, A.L.; Smart, J.A.; Hawke, L.G.; Moore, S.D.; Renaud, S.J.; Soares, M.J.; Morrell, N.W.; Ormiston, M.L. Impaired interleukin-15 signaling via BMPR2 loss drives natural killer cell deficiency and pulmonary hypertension. Hypertension, 2022, 79(11), 2493-2504.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.122.19178] [PMID: 36043416]
[78]
Choi, Y.J.; Lee, H.; Kim, J.H.; Kim, S.Y.; Koh, J.Y.; Sa, M.; Park, S.H.; Shin, E.C. CD5 suppresses IL-15–induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways. J. Immunol., 2022, 209(6), 1108-1117.
[http://dx.doi.org/10.4049/jimmunol.2100854] [PMID: 36002232]
[79]
Ma, S.; Tang, T.; Wu, X.; Mansour, A.G.; Lu, T.; Zhang, J.; Wang, L.S.; Caligiuri, M.A.; Yu, J. PDGF-D−PDGFRβ signaling enhances IL-15–mediated human natural killer cell survival. Proc. Natl. Acad. Sci. USA, 2022, 119(3), e2114134119.
[http://dx.doi.org/10.1073/pnas.2114134119] [PMID: 35027451]
[80]
Raeber, M.E.; Sahin, D.; Boyman, O. Interleukin-2–based therapies in cancer. Sci. Transl. Med., 2022, 14(670), eabo5409.
[http://dx.doi.org/10.1126/scitranslmed.abo5409] [PMID: 36350987]
[81]
Reardon, S. How to supercharge cancer-fighting cells: give them stem-cell skills. Nature, 2024, 628(8008), 486.
[http://dx.doi.org/10.1038/d41586-024-01043-2] [PMID: 38600202]
[82]
Chapoval, A.I.; Fuller, J.A.; Kremlev, S.G.; Kamdar, S.J.; Evans, R. Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells. J. Immunol., 1998, 161(12), 6977-6984.
[http://dx.doi.org/10.4049/jimmunol.161.12.6977] [PMID: 9862733]
[83]
Van Belle, T.; Grooten, J. IL-15 and IL-15Ralpha in CD4+T cell immunity. Arch. Immunol. Ther. Exp. (Warsz.), 2005, 53(2), 115-126.
[PMID: 15928580]
[84]
Bergamaschi, C.; Pandit, H.; Nagy, B.A.; Stellas, D.; Jensen, S.M.; Bear, J.; Cam, M.; Valentin, A.; Fox, B.A.; Felber, B.K.; Pavlakis, G.N. Heterodimeric IL-15 delays tumor growth and promotes intratumoral CTL and dendritic cell accumulation by a cytokine network involving XCL1, IFN-γ, CXCL9 and CXCL10. J. Immunother. Cancer, 2020, 8(1), e000599.
[http://dx.doi.org/10.1136/jitc-2020-000599] [PMID: 32461349]
[85]
Rubinstein, M.P.; Kovar, M.; Purton, J.F.; Cho, J.H.; Boyman, O.; Surh, C.D.; Sprent, J. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl. Acad. Sci. USA, 2006, 103(24), 9166-9171.
[http://dx.doi.org/10.1073/pnas.0600240103] [PMID: 16757567]
[86]
Zhu, X.; Marcus, W.D.; Xu, W.; Lee, H.; Han, K.; Egan, J.O.; Yovandich, J.L.; Rhode, P.R.; Wong, H.C. Novel human interleukin-15 agonists. J. Immunol., 2009, 183(6), 3598-3607.
[http://dx.doi.org/10.4049/jimmunol.0901244] [PMID: 19710453]
[87]
Waldmann, T.A.; Dubois, S.; Miljkovic, M.D.; Conlon, K.C. IL-15 in the combination immunotherapy of cancer. Front. Immunol., 2020, 11, 868.
[http://dx.doi.org/10.3389/fimmu.2020.00868] [PMID: 32508818]
[88]
Shen, J.; Zou, Z.; Guo, J.; Cai, Y.; Xue, D.; Liang, Y.; Wang, W.; Peng, H.; Fu, Y.X. An engineered concealed IL-15-R elicits tumor-specific CD8+T cell responses through PD-1-cis delivery. J. Exp. Med., 2022, 219(12), e20220745.
[http://dx.doi.org/10.1084/jem.20220745] [PMID: 36165896]
[89]
Hirayama, A.V.; Chou, C.K.; Miyazaki, T.; Steinmetz, R.N.; Di, H.A.; Fraessle, S.P.; Gauthier, J.; Fiorenza, S.; Hawkins, R.M.; Overwijk, W.W.; Riddell, S.R.; Marcondes, M.Q.; Turtle, C.J. A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR T-cell immunotherapy. Blood Adv., 2023, 7(11), 2479-2493.
[http://dx.doi.org/10.1182/bloodadvances.2022008697] [PMID: 36332004]
[90]
Mujib, S.; Jones, R.B.; Lo, C.; Aidarus, N.; Clayton, K.; Sakhdari, A.; Benko, E.; Kovacs, C.; Ostrowski, M.A. Antigen-independent induction of Tim-3 expression on human T cells by the common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 is associated with proliferation and is dependent on the phosphoinositide 3-kinase pathway. J. Immunol., 2012, 188(8), 3745-3756.
[http://dx.doi.org/10.4049/jimmunol.1102609] [PMID: 22422881]
[91]
Conlon, K.C.; Lugli, E.; Welles, H.C.; Rosenberg, S.A.; Fojo, A.T.; Morris, J.C.; Fleisher, T.A.; Dubois, S.P.; Perera, L.P.; Stewart, D.M.; Goldman, C.K.; Bryant, B.R.; Decker, J.M.; Chen, J.; Worthy, T.Y.A.; Figg, W.D., Sr; Peer, C.J.; Sneller, M.C.; Lane, H.C.; Yovandich, J.L.; Creekmore, S.P.; Roederer, M.; Waldmann, T.A. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol., 2015, 33(1), 74-82.
[http://dx.doi.org/10.1200/JCO.2014.57.3329] [PMID: 25403209]
[92]
Romee, R.; Cooley, S.; Berrien-Elliott, M.M.; Westervelt, P.; Verneris, M.R.; Wagner, J.E.; Weisdorf, D.J.; Blazar, B.R.; Ustun, C.; DeFor, T.E.; Vivek, S.; Peck, L.; DiPersio, J.F.; Cashen, A.F.; Kyllo, R.; Musiek, A.; Schaffer, A.; Anadkat, M.J.; Rosman, I.; Miller, D.; Egan, J.O.; Jeng, E.K.; Rock, A.; Wong, H.C.; Fehniger, T.A.; Miller, J.S. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood, 2018, 131(23), 2515-2527.
[http://dx.doi.org/10.1182/blood-2017-12-823757] [PMID: 29463563]
[93]
Liu, R.B.; Engels, B.; Schreiber, K.; Ciszewski, C.; Schietinger, A.; Schreiber, H.; Jabri, B. IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc. Natl. Acad. Sci. USA, 2013, 110(20), 8158-8163.
[http://dx.doi.org/10.1073/pnas.1301022110] [PMID: 23637340]
[94]
Di Matteo, S.; Munari, E.; Fiore, P.F.; Santopolo, S.; Sampaoli, C.; Pelosi, A.; Chouaib, S.; Tumino, N.; Vacca, P.; Mariotti, F.R.; Ebert, S.; Machwirth, M.; Haas, D.; Pezzullo, M.; Pietra, G.; Grottoli, M.; Buart, S.; Mortier, E.; Maggi, E.; Moretta, L.; Caruana, I.; Azzarone, B. The roles of different forms of IL-15 in human melanoma progression. Front. Immunol., 2023, 14, 1183668.
[http://dx.doi.org/10.3389/fimmu.2023.1183668] [PMID: 37334356]
[95]
Fehniger, T.A.; Caligiuri, M.A. Interleukin 15: biology and relevance to human disease. Blood, 2001, 97(1), 14-32.
[http://dx.doi.org/10.1182/blood.V97.1.14] [PMID: 11133738]
[96]
Yuan, H.; Meng, X.; Guo, W.; Cai, P.; Li, W.; Li, Q.; Wang, W.; Sun, Y.; Xu, Q.; Gu, Y. Transmembrane-bound IL-15–promoted epithelial-mesenchymal transition in renal cancer cells requires the Src-dependent Akt/GSK-3β/β-catenin pathway. Neoplasia, 2015, 17(5), 410-420.
[http://dx.doi.org/10.1016/j.neo.2015.04.002] [PMID: 26025664]
[97]
Azzi, S.; Gallerne, C.; Romei, C.; Le Coz, V.; Gangemi, R.; Khawam, K.; Devocelle, A.; Gu, Y.; Bruno, S.; Ferrini, S.; Chouaib, S.; Eid, P.; Azzarone, B.; Giron-Michel, J. Human renal normal, tumoral, and cancer stem cells express membrane-bound interleukin-15 isoforms displaying different functions. Neoplasia, 2015, 17(6), 509-517.
[http://dx.doi.org/10.1016/j.neo.2015.06.002] [PMID: 26152359]
[98]
Guo, J.; Liang, Y.; Xue, D.; Shen, J.; Cai, Y.; Zhu, J.; Fu, Y.X.; Peng, H. Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity. Cell Res., 2021, 31(11), 1190-1198.
[http://dx.doi.org/10.1038/s41422-021-00543-4] [PMID: 34376814]
[99]
Wrangle, J.M.; Velcheti, V.; Patel, M.R.; Garrett-Mayer, E.; Hill, E.G.; Ravenel, J.G.; Miller, J.S.; Farhad, M.; Anderton, K.; Lindsey, K.; Taffaro-Neskey, M.; Sherman, C.; Suriano, S.; Swiderska-Syn, M.; Sion, A.; Harris, J.; Edwards, A.R.; Rytlewski, J.A.; Sanders, C.M.; Yusko, E.C.; Robinson, M.D.; Krieg, C.; Redmond, W.L.; Egan, J.O.; Rhode, P.R.; Jeng, E.K.; Rock, A.D.; Wong, H.C.; Rubinstein, M.P. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol., 2018, 19(5), 694-704.
[http://dx.doi.org/10.1016/S1470-2045(18)30148-7] [PMID: 29628312]
[100]
Brammer, J.E.; Ballen, K.; Sokol, L.; Querfeld, C.; Nakamura, R.; Mishra, A.; McLaughlin, E.M.; Feith, D.; Azimi, N.; Waldmann, T.A.; Tagaya, Y.; Loughran, T. Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia. Blood, 2023, 142(15), 1271-1280.
[http://dx.doi.org/10.1182/blood.2022017643] [PMID: 37352612]
[101]
Slavuljica, I.; Krmpotić, A.; Jonjić, S. Manipulation of NKG2D ligands by cytomegaloviruses: impact on innate and adaptive immune response. Front. Immunol., 2011, 2, 85.
[PMID: 22566874]