Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV

Abstract

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body’s immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CARmodified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CARmodified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.

Keywords

natural killer cell / chimeric antigen receptor / immunotherapy / immunological synapse / HIV / cancer

References

[1] Ada G (1994) Twenty years into the saga of MHC-restriction. Immunol Cell Biol 72:447–454

[2] Adams NM, O’Sullivan TE, Geary CD, Karo JM, Amezquita RA, Joshi NS, Kaech SM, Sun JC (2016) NK cell responses redefine immunological memory. J Immunol 197:2963–2970

[3] Aggen DH, Chervin AS, Schmitt TM, Engels B, Stone JD, Richman SA, Piepenbrink KH, Baker BM, Greenberg PD, Schreiber H (2012) Single-chain Valpha Vbeta T-cell receptors function without mispairing with endogenous TCR chains. Gene Ther 19:365–374

[4] Akl MR, Nagpal P, Ayoub NM, Prabhu SA, Gliksman M, Tai B, Hatipoglu A, Goy A, Suh KS (2015) Molecular and clinical profiles of syndecan-1 in solid and hematological cancer for prognosis and precision medicine. Oncotarget 6:28693–28715

[5] Ali A, Kitchen SG, Chen IS, Ng HL, Zack JA, Yang OO (2016) HIV-1-specific chimeric antigen receptors based on broadly neutralizing antibodies. J Virol 90:6999–7006

[6] Alter G, Altfeld M (2006) NK cell function in HIV-1 infection. Curr Mol Med 6:621–629

[7] Alter G, Altfeld M (2009) NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J Intern Med 265:29–42

[8] Alter G, Altfeld M (2011) Mutiny or scrutiny: NK cell modulation of DC function in HIV-1 infection. Trends Immunol 32:219–224

[9] Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A, Streeck H, Waring M, Meier A, Brander C (2007) Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 204:3027–3036

[10] Alter G, Heckerman D, Schneidewind A, Fadda L, Kadie CM, Carlson JM, Oniangue-Ndza C, Martin M, Li B, Khakoo SI (2011) HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476:96–100

[11] Altfeld M, Gale M Jr (2015) Innate immunity against HIV-1 infection. Nat Immunol 16:554–562

[12] Altfeld M, Fadda L, Frleta D, Bhardwaj N (2011) DCs and NK cells: critical effectors in the immune response to HIV-1. Nat Rev Immunol 11:176–186

[13] Anikeeva N, Somersalo K, Sims TN, Thomas VK, Dustin ML, Sykulev Y (2005) Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 102:6437–6442

[14] Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H (2008) Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10:625–632

[15] Bakker AB, Wu J, Phillips JH, Lanier LL (2000) NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals. Hum Immunol 61:18–27

[16] Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK (2010) The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116:2286–2294

[17] Bernstein HB, Wang G, Plasterer MC, Zack JA, Ramasastry P, Mumenthaler SM, Kitchen CM (2009) CD4+ NK cells can be productively infected with HIV, leading to downregulation of CD4 expression and changes in function . Virology 387:59–66

[18] Bertolet G, Liu D (2016) The planar lipid bilayer system serves as a reductionist approach for studying NK cell immunological synapses and their functions. Methods Mol Biol 1441:151–165

[19] Bhaumik S, Gambhir SS (2002) Optical imaging of Renilla luciferase reporter gene expression in living mice. Proc Natl Acad Sci U S A 99:377–382

[20] Biron CA, Byron KS, Sullivan JL (1989) Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320:1731–1735

[21] Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, Klingemann H (2013) Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. Oncoimmunology 2:e26527

[22] Borges da Silva H, Fonseca R, Alvarez JM, D’Imperio Lima MR (2015) IFN-gamma priming effects on the maintenance of effector memory CD4(+) T cells and on phagocyte function: evidences from infectious diseases. J Immunol Res 2015:202816

[23] Bromley SK, Burack WR, Johnson KG, Somersalo K, Sims TN, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (2001) The immunological synapse. Annu Rev Immunol 19:375–396

[24] Bryceson YT, Ljunggren HG (2008) Tumor cell recognition by the NK cell activating receptor NKG2D. Eur J Immunol 38:2957–2961

[25] Buck MD, O’Sullivan D, Pearce EL (2015) T cell metabolism drives immunity. J Exp Med 212:1345–1360

[26] Burke S, Lakshmikanth T, Colucci F, Carbone E (2010) New views on natural killer cell-based immunotherapy for melanoma treatment. Trends Immunol 31:339–345

[27] Campbell KS, Yusa S, Kikuchi-Maki A, Catina TL (2004) NKp44 triggers NK cell activation through DAP12 association that is not influenced by a putative cytoplasmic inhibitory sequence. J Immunol 172:899–906

[28] Campi G, Varma R, Dustin ML (2005) Actin and agonist MHCpeptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med 202:1031–1036

[29] Carr WH, Rosen DB, Arase H, Nixon DF, Michaelsson J, Lanier LL (2007) Cutting edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. J Immunol 178:647–651

[30] Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A (2003) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 100:4120–4125

[31] Chehimi J, Bandyopadhyay S, Prakash K, Perussia B, Hassan NF, Kawashima H, Campbell D, Kornbluth J, Starr SE (1991) In vitro infection of natural killer cells with different human immunodeficiency virus type 1 isolates. J Virol 65:1812–1822

[32] Chen X, Han J, Chu J, Zhang L, Zhang J, Chen C, Chen L, Wang Y, Wang H, Yi L (2016) A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 7:27764–27777

[33] Chen KH, Wada M, Pinz KG, Liu H, Lin KW, Jares A, Firor AE, Shuai X, Salman H, Golightly M (2017) Preclinical targeting of aggressive T cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia.

[34] Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS (2016) Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 126:3130–3144

[35] Cho FN, Chang TH, Shu CW, Ko MC, Liao SK, Wu KH, Yu MS, Lin SJ, Hong YC, Chen CH (2014) Enhanced cytotoxicity of natural killer cells following the acquisition of chimeric antigen receptors through trogocytosis. PLoS ONE 9:e109352

[36] Choi YS, Yang JA, Yusuf I, Johnston RJ, Greenbaum J, Peters B, Crotty S (2013) Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J Immunol 190:4014–4026

[37] Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, Boucher G, Boulassel MR, Ghattas G, Brenchley JM (2009) HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15:893–900

[38] Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine B, June CH, Schuster SJ (2016) PD-1 blockade modulates chimeric antigen receptor (CAR) modified T cells and induces tumor regression: refueling the CAR. Blood 129 (8):1039–1041

[39] Choudhuri K, Llodra J, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL, Dustin ML (2014) Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118–123

[40] Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, Peng Y, Mao H, Yi L, Ghoshal K (2014) CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28:917–927

[41] Chung A, Rollman E, Johansson S, Kent SJ, Stratov I (2008) The utility of ADCC responses in HIV infection. Curr HIV Res 6:515–519

[42] Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R (2016) HIV reservoirs: what, where and how to target them. Nat Rev Microbiol 14:55–60

[43] Cohen GB, Gandhi RT, Davis DM, Mandelboim O, Chen BK, Strominger JL, Baltimore D (1999) The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10:661–671

[44] Cong L, Zhang F (2015) Genome engineering using CRISPR-Cas9 system. Methods Mol Biol 1239:197–217

[45] Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823

[46] Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D, Gastaut JA, Pende D, Olive D, Moretta A (2002) Defective expression and function of natural killer celltriggering receptors in patients with acute myeloid leukemia. Blood 99:3661–3667

[47] Curti A, Ruggeri L, D’Addio A, Bontadini A, Dan E, Motta MR, Trabanelli S, Giudice V, Urbani E, Martinelli G (2011) Successful transfer of alloreactive haploidentical KIR ligandmismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118:3273–3279

[48] Davis DM (2002) Assembly of the immunological synapse for T cells and NK cells. Trends Immunol 23:356–363

[49] Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL (1999) The human natural killer cell immune synapse. Proc Natl Acad Sci U S A 96:15062–15067

[50] De Maria A, Moretta L (2008) NK cell function in HIV-1 infection. Curr HIV Res 6:433–440

[51] Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Di Mascio M, Katlama C (2012) Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 12:607–614

[52] Della Chiesa M, Romeo E, Falco M, Balsamo M, Augugliaro R, Moretta L, Bottino C, Moretta A, Vitale M (2008) Evidence that the KIR2DS5 gene codes for a surface receptor triggering natural killer cell function. Eur J Immunol 38:2284–2289

[53] Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, Singh H, Hurton L, Maiti SN, Huls MH (2012) Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 7:e30264

[54] DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A (2014) Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64:252–271

[55] DeSantis CE, Siegel RL, Sauer AG, Miller KD, Fedewa SA, Alcaraz KI, Jemal A (2016) Cancer statistics for African Americans, 2016: progress and opportunities in reducing racial disparities. CA Cancer J Clin.

[56] Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B (2011) Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 365:1673–1683

[57] Dustin ML, Long EO (2010) Cytotoxic immunological synapses. Immunol Rev 235:24–34

[58] Dustin ML, Starr T, Varma R, Thomas VK (2007) Unit 18 13 Supported planar bilayers for study of the immunological synapse. Curr Protoc Immunol.

[59] Esser R, Muller T, Stefes D, Kloess S, Seidel D, Gillies SD, Aperlo-Iffland C, Huston JS, Uherek C, Schonfeld K (2012) NK cells engineered to express a GD2-specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. J Cell Mol Med 16:569–581

[60] Fadda L, Alter G (2011) KIR/HLA: genetic clues for a role of NK cells in the control of HIV. Adv Exp Med Biol 780:27–36

[61] Farnault L, Sanchez C, Baier C, Le Treut T, Costello RT (2012) Hematological malignancies escape from NK cell innate immune surveillance: mechanisms and therapeutic implications. Clin Dev Immunol 2012:421702

[62] Fauci AS, Mavilio D, Kottilil S (2005) NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol 5:835–843

[63] Fehniger TA, Cooper MA (2016) Harnessing NK cell memory for cancer immunotherapy. Trends Immunol 37:877–888

[64] Fooksman DR, Vardhana S, Vasiliver-Shamis G, Liese J, Blair DA, Waite J, Sacristan C, Victora GD, Zanin-Zhorov A, Dustin ML (2010) Functional anatomy of T cell activation and synapse formation. Annu Rev Immunol 28:79–105

[65] Funke J, Durr R, Dietrich U, Koch J (2011) Natural killer cells in HIV-1 infection: a double-edged sword. AIDS Rev 13:67–76

[66] Gargett T, Yu W, Dotti G, Yvon ES, Christo SN, Hayball JD, Lewis ID, Brenner MK, Brown MP (2016) GD2-specific CAR T Cells undergo potent activation and deletion following antigen encounter but can be protected from activation-induced cell death by PD-1 blockade. Mol Ther 24:1135–1149

[67] Geldres C, Savoldo B, Dotti G (2016) Chimeric antigen receptorredirected T cells return to the bench. Semin Immunol 28(1):3–9

[68] Gilham DE, Debets R, Pule M, Hawkins RE, Abken H (2012) CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol Med 18:377–384

[69] Gill S, June CH (2015) Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev 263:68–89

[70] Gill S, Maus MV, Porter DL (2016) Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev 30:157–167

[71] Gleason MK, Ross JA, Warlick ED, Lund TC, Verneris MR, Wiernik A, Spellman S, Haagenson MD, Lenvik AJ, Litzow MR (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123:3016–3026

[72] Glienke W, Esser R, Priesner C, Suerth JD, Schambach A, Wels WS, Grez M, Kloess S, Arseniev L, Koehl U (2015) Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol 6:21

[73] Gong JH, Maki G, Klingemann HG (1994) Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652–658

[74] Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–227

[75] Gras Navarro A, Bjorklund AT, Chekenya M (2015) Therapeutic potential and challenges of natural killer cells in treatment of solid tumors. Front Immunol 6:202

[76] Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibodytype specificity. Proc Natl Acad Sci U S A 86:10024–10028

[77] Guerrero AD, Moyes JS, Cooper LJ (2014) The human application of gene therapy to re-program T-cell specificity using chimeric antigen receptors. Chin J Cancer 33:421–433

[78] Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, Victor A, Meisen WH, Kim SH, Grandi P (2015) CAR-engineered NK Cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep 5:11483

[79] Harwood NE, Batista FD (2010) Early events in B cell activation. Annu Rev Immunol 28:185–210

[80] Hatano H, Jain V, Hunt PW, Lee TH, Sinclair E, Do TD, Hoh R, Martin JN, McCune JM, Hecht F (2013) Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. J Infect Dis 208:50–56

[81] Hayley M, Bourbigot S, Booth V (2011) Self-association of an activating natural killer cell receptor, KIR2DS1. PLoS ONE 6: e23052

[82] Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R (2012) Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 366:1275–1286

[83] Hens J, Jennes W, Kestens L (2016) The role of NK cells in HIV-1 protection: autologous, allogeneic or both? AIDS Res Ther 13:15

[84] Herberman RB, Nunn ME, Holden HT, Lavrin DH (1975a) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 16:230–239

[85] Herberman RB, Nunn ME, Lavrin DH (1975b) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer 16:216–229

[86] Hermanson DL, Kaufman DS (2015) Utilizing chimeric antigen receptors to direct natural killer cell activity. Front Immunol 6:195

[87] Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y (2008) CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 14:2775–2784

[88] Iannello A, Debbeche O, Samarani S, Ahmad A (2008a) Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS. J Leukoc Biol 84:1–26

[89] Iannello A, Debbeche O, Samarani S, Ahmad A (2008b) Antiviral NK cell responses in HIV infection: II. Viral strategies for evasion and lessons for immunotherapy and vaccination. J Leukoc Biol 84:27–49

[90] Jang JH, Huang Y, Zheng P, Jo MC, Bertolet G, Zhu MX, Qin L, Liu D (2015) Imaging of cell-cell communication in a vertical orientation reveals high-resolution structure of immunological synapse and novel PD-1 dynamics. J Immunol 195:1320–1330

[91] Jenkins MR, Tsun A, Stinchcombe JC, Griffiths GM (2009) The strength of T cell receptor signal controls the polarization of cytotoxic machinery to the immunological synapse. Immunity 31:621–631

[92] Jiang H, Zhang W, Shang P, Zhang H, Fu W, Ye F, Zeng T, Huang H, Zhang X, Sun W (2014) Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol Oncol 8:297–310

[93] John LB, Kershaw MH, Darcy PK (2013) Blockade of PD-1 immunosuppression boosts CAR T-cell therapy. Oncoimmunology 2:e26286

[94] Jones RB, Walker BD (2016) HIV-specific CD8(+) T cells and HIV eradication. J Clin Invest 126:455–463

[95] Jost S, Altfeld M (2012) Evasion from NK cell-mediated immune responses by HIV-1. Microbes Infect 14:904–915

[96] Jost S, Altfeld M (2013) Control of human viral infections by natural killer cells. Annu Rev Immunol 31:163–194

[97] Karre K, Ljunggren HG, Piontek G, Kiessling R (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675–678

[98] Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704

[99] Kershaw MH, Teng MW, Smyth MJ, Darcy PK (2005) Supernatural T cells: genetic modification of T cells for cancer therapy. Nat Rev Immunol 5:928–940

[100] Kiessling R, Klein E, Pross H, Wigzell H (1975a) “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur J Immunol 5:117–121

[101] Kiessling R, Klein E, Wigzell H (1975b) “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype . Eur J Immunol 5:112–117

[102] Kim YJ, Dubey P, Ray P, Gambhir SS, Witte ON (2004) Multimodality imaging of lymphocytic migration using lentiviral-based transduction of a tri-fusion reporter gene. Mol Imaging Biol 6:331–340

[103] Kim MG, Kim D, Suh SK, Park Z, Choi MJ, Oh YK (2016) Current status and regulatory perspective of chimeric antigen receptormodified T cell therapeutics. Arch Pharm Res 39:437–452

[104] Klingemann H, Boissel L, Toneguzzo F (2016) Natural killer cells for immunotherapy- advantages of the NK-92 cell line over blood NK cells. Front Immunol 7:91

[105] Kramski M, Parsons MS, Stratov I, Kent SJ (2013) HIV-specific antibody immunity mediated through NK cells and monocytes. Curr HIV Res 11:388–406

[106] Krockenberger M, Dombrowski Y, Weidler C, Ossadnik M, Honig A, Hausler S, Voigt H, Becker JC, Leng L, Steinle A (2008) Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D. J Immunol 180:7338–7348

[107] Kyle RA, Rajkumar SV (2008) Multiple myeloma. Blood 111:2962–2972

[108] Lagrue K, Carisey A, Oszmiana A, Kennedy PR, Williamson DJ, Cartwright A, Barthen C, Davis DM (2013) The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse. Immunol Rev 256:203–221

[109] Lam VC, Lanier LL (2016) NK cells in host responses to viral infections. Curr Opin Immunol 44:43–51

[110] Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274

[111] Lanier LL, Corliss B, Wu J, Phillips JH (1998a) Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8:693–701

[112] Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH (1998b) Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391:703–707

[113] Lapteva N, Parihar R, Rollins LA, Gee AP, Rooney CM (2016) Largescale culture and genetic modification of human natural killer cells for cellular therapy. Methods Mol Biol 1441:195–202

[114] Le Bert N, Gasser S (2014) Advances in NKG2D ligand recognition and responses by NK cells. Immunol Cell Biol 92:230–236

[115] Lee KH, Holdorf AD, Dustin ML, Chan AC, Allen PM, Shaw AS (2002) T cell receptor signaling precedes immunological synapse formation. Science 295:1539–1542

[116] Lee KH, Dinner AR, Tu C, Campi G, Raychaudhuri S, Varma R, Sims TN, Burack WR, Wu H, Wang J (2003) The immunological synapse balances T cell receptor signaling and degradation. Science 302:1218–1222

[117] Lim WA, June CH (2017) The principles of engineering immune cells to treat cancer. Cell 168:724–740

[118] Lisovsky I, Isitman G, Song R, DaFonseca S, Tremblay-McLean A, Lebouche B, Routy JP, Bruneau J, Bernard NF (2015) A higher frequency of NKG2A+ than of NKG2A- NK cells responds to autologous HIV-infected CD4 cells irrespective of whether or not they coexpress KIR3DL1. J Virol 89:9909–9919

[119] Liu D, Bryceson YT, Meckel T, Vasiliver-Shamis G, Dustin ML, Long EO (2009) Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31:99–109

[120] Liu D, Peterson ME, Long EO (2012) The adaptor protein Crk controls activation and inhibition of natural killer cells. Immunity 36:600–611

[121] Liu L, Patel B, Ghanem MH, Bundoc V, Zheng Z, Morgan RA, Rosenberg SA, Dey B, Berger EA (2015) Novel CD4-based bispecific chimeric antigen receptor designed for enhanced anti-HIV potency and absence of HIV entry receptor activity. J Virol 89:6685–6694

[122] Liu B, Zou F, Lu L, Chen C, He D, Zhang X, Tang X, Liu C, Li L, Zhang H (2016) Chimeric antigen receptor T cells guided by the single-chain Fv of a broadly neutralizing antibody specifically and effectively eradicate virus reactivated from latency in CD4+ T lymphocytes isolated from HIV-1-infected individuals receiving suppressive combined antiretroviral therapy. J Virol 90:9712–9724

[123] Liu H, Pa n Y, Meng S, Zhang W, Zhou F (2017a) Current treatment options of T cell-associated immunotherapy in multiple myeloma. Clin Exp Med.

[124] Liu X, Zhang Y, Cheng C, Cheng AW, Zhang X, Li N, Xia C, Wei X, Liu X, Wang H (2017b) CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res 27:154–157

[125] Ljunggren HG, Karre K (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11:237–244

[126] Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84

[127] Long BR, Ndhlovu LC, Oksenberg JR, Lanier LL, Hecht FM, Nixon DF, Barbour JD (2008) Conferral of enhanced natural killer cell function by KIR3DS1 in early human immunodeficiency virus type 1 infection. J Virol 82:4785–4792

[128] Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S (2013) Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 31:227–258

[129] Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR (2015) 4-1BB costimulation ameliorates Tcell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21:581–590

[130] Luetkens T, Yousef S, Radhakrishnan SV, Atanackovic D (2017) Current strategies for the immunotherapy of multiple myeloma. Oncology (Williston Park) 31(1):55–63

[131] Magana-Maldonado R, Chavez-Cortez EG, Olascoaga-Arellano NK, Lopez-Mejia M, Maldonado-Leal FM, Sotelo J, Pineda B (2016) Immunological evasion in glioblastoma. Biomed Res Int 2016:7487313

[132] Maiti SN, Huls H, Singh H, Dawson M, Figliola M, Olivares S, Rao P, Zhao YJ, Multani A, Yang G (2013) Sleeping beauty system to redirect T-cell specificity for human applications. J Immunother 36:112–123

[133] Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L, Moretta A (2005) IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. J Immunol 174:3992–3998

[134] Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ, Buchbinder S, Hoots K, Vlahov D, Trowsdale J (2002) Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 31:429–434

[135] Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, Weiss WA (2016) Neuroblastoma. Nat Rev Dis Primers 2:16078

[136] Maude S, Barrett DM (2016) Current status of chimeric antigen receptor therapy for haematological malignancies. Br J Haematol 172:11–22

[137] Mavilio D, Benjamin J, Daucher M, Lombardo G, Kottilil S, Planta MA, Marcenaro E, Bottino C, Moretta L, Moretta A (2003) Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates. Proc Natl Acad Sci U S A 100:15011–15016

[138] McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF (2010) The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 10:11–23

[139] Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105:3051–3057

[140] Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A (1998) Threedimensional segregation of supramolecular activation clusters in T cells. Nature 395:82–86

[141] Morse D, Tannous BA (2012) A water-soluble coelenterazine for sensitive in vivo imaging of coelenterate luciferases. Mol Ther 20:692–693

[142] Morvan MG, Lanier LL (2016) NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16:7–19

[143] Mossman KD, Campi G, Groves JT, Dustin ML (2005) Altered TCR signaling from geometrically repatterned immunological synapses. Science 310:1191–1193

[144] Mzingwane ML, Tiemessen CT (2017) Mechanisms of HIV persistence in HIV reservoirs. Rev Med Virol.

[145] Oelsner S, Friede ME, Zhang C,Wagner J, Badura S, Bader P, Ullrich E, Ottmann OG, Klingemann H, Tonn T (2017) Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Cytotherapy 19:235–249

[146] Ogasawara K, Lanier LL (2005) NKG2D in NK and T cell-mediated immunity. J Clin Immunol 25:534–540

[147] Orange JS (2008) Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol 8:713–725

[148] Orange JS (2013) Natural killer cell deficiency. J Allergy Clin Immunol 132, 515–525; quiz 526.

[149] Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, Holmberg SD, Investigators HIVOS (2006) Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 43:27–34

[150] Pallikkuth S, Sharkey M, Babic DZ, Gupta S, Stone GW, Fischl MA, Stevenson M, Pahwa S (2015) Peripheral T follicular helper cells are the major HIV reservoir within central memory CD4 T cells in peripheral blood from chronic HIV infected individuals on cART. J Virol 90(6):2718–2728

[151] Pascal V, Yamada E, Martin MP, Alter G, Altfeld M, Metcalf JA, Baseler MW, Adelsberger JW, Carrington M, Anderson SK (2007) Detection of KIR3DS1 on the cell surface of peripheral blood NK cells facilitates identification of a novel null allele and assessment of KIR3DS1 expression during HIV-1 infection. J Immunol 179:1625–1633

[152] Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R, Haddad EK, De Leval L, Graziosi C, Pantaleo G (2013) Follicular helper Tcells serve as the major CD4 Tcell compartment for HIV-1 infection, replication, and production. J Exp Med 210:143–156

[153] Pietra G, Vitale C, Pende D, Bertaina A, Moretta F, Falco M, Vacca P, Montaldo E, Cantoni C, Mingari MC (2016) Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias. Cancer Immunol Immunother 65:465–476

[154] Ping Y, Liu C, Zhang Y (2017) T-cell receptor-engineered T cells for cancer treatment: current status and future directions. Protein Cell.

[155] Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733

[156] Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y (2016) Multiplex genome editing to generate universal CAR Tcells resistant to PD1 inhibition. Clin Cancer Res.

[157] Rezvani K, Rouce RH (2015) The application of natural killer cell immunotherapy for the treatment of cancer. Front Immunol 6:578

[158] Richard J, Sindhu S, Pham TN, Belzile JP, Cohen EA (2010) HIV-1 Vpr up-regulates expressionof ligandsfor theactivatingNKG2Dreceptor and promotes NK cell-mediated killing. Blood 115:1354–1363

[159] Robertson MJ, Cochran KJ, Cameron C, Le JM, Tantravahi R, Ritz J (1996) Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia. Exp Hematol 24:406–415

[160] Rosenberg EB, McCoy JL, Green SS, Donnelly FC, Siwarski DF, Levine PH, Herberman RB (1974) Destruction of human lymphoid tissue-culture cell lines by human peripheral lymphocytes in 51Cr-release cellular cytotoxicity assays. J Natl Cancer Inst 52:345–352

[161] Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA (2016) Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164:770–779

[162] Rydyznski C, Daniels KA, Karmele EP, Brooks TR, Mahl SE, Moran MT, Li C, Sutiwisesak R, Welsh RM, Waggoner SN (2015) Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells. Nat Commun 6:6375

[163] Sadelain M (2011) Eliminating cells gone astray. N Engl J Med 365:1735–1737

[164] Schonfeld K, Sahm C, Zhang C, Naundorf S, Brendel C, Odendahl M, Nowakowska P, Bonig H, Kohl U, Kloess S (2015) Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther 23:330–338

[165] Scott-Algara D, Vuillier F, Cayota A, Rame V, Guetard D, Moncany ML, Marasescu M, Dauguet C, Dighiero G (1993) In vitro nonproductive infection of purified natural killer cells by the BRU isolate of the human immunodeficiency virus type 1. J Gen Virol 74(Pt 4):725–731

[166] Scully E, Alter G (2016) NK cells in HIV disease. Curr HIV/AIDS Rep 13:85–94

[167] Shimizu Y, Geraghty DE, Koller BH, Orr HT, DeMars R (1988) Transfer and expression of three cloned human non-HLA-A, B, C class I major histocompatibility complex genes in mutant lymphoblastoid cells. Proc Natl Acad Sci U S A 85:227–231

[168] Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30

[169] Siliciano RF (2014) Opening fronts in HIV vaccine development: targeting reservoirs to clear and cure. Nat Med 20:480–481

[170] Singh H, Huls H, Kebriaei P, Cooper LJ (2014) A new approach to gene therapy using sleeping beauty to genetically modify clinical-grade T cells to target CD19. Immunol Rev 257:181–190

[171] Smith KM, Wu J, Bakker AB, Phillips JH, Lanier LL (1998) Ly-49D and Ly-49H associate with mouse DAP12 and form activating receptors. J Immunol 161:7–10

[172] Stinchcombe JC, Griffiths GM (2003) The role of the secretory immunological synapse in killing by CD8+ CTL. Semin Immunol 15:301–305

[173] Stinchcombe JC, Majorovits E, Bossi G, Fuller S, Griffiths GM (2006) Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443:462–465

[174] Sun JC, Lopez-Verges S, Kim CC, DeRisi JL, Lanier LL (2011) NK cells and immune “memory”. J Immunol 186:1891–1897

[175] Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, Lee AI, Podar K, Hideshima T, Rice AG (2008) Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112:1329–1337

[176] Talmadge JE, Meyers KM, Prieur DJ, Starkey JR (1980) Role of natural killer cells in tumor growth and metastasis: C57BL/6 normal and beige mice. J Natl Cancer Inst 65:929–935

[177] Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, Suttorp M, Seifried E, Ottmann OG, Bug G (2013) Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 15:1563–1570

[178] Topfer K, Cartellieri M, Michen S, Wiedemuth R, Muller N, Lindemann D, Bachmann M, Fussel M, Schackert G, Temme A (2015) DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. J Immunol 194:3201–3212

[179] Torre LA, Sauer AM, Chen MS Jr, Kagawa-Singer M, Jemal A, Siegel RL (2016) Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: converging incidence in males and females. CA Cancer J Clin.

[180] Tozeren A, Sung KL, Sung LA, Dustin ML, Chan PY, Springer TA, Chien S (1992) Micromanipulation of adhesion of a Jurkat cell to a planar bilayer membrane containing lymphocyte functionassociated antigen 3 molecules. J Cell Biol 116:997–1006

[181] Tran AC, Zhang D, Byrn R, Roberts MR (1995) Chimeric zetareceptors direct human natural killer (NK) effector function to permit killing of NK-resistant tumor cells and HIV-infected T lymphocytes. J Immunol 155:1000–1009

[182] Travar M, Petkovic M, Verhaz A (2016) Type I, II, and III interferons: regulating immunity to mycobacterium tuberculosis Infection. Arch Immunol Ther Exp (Warsz) 64:19–31

[183] Valentin A, Rosati M, Patenaude DJ, Hatzakis A, Kostrikis LG, Lazanas M, Wyvill KM, Yarchoan R, Pavlakis GN (2002) Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc Natl Acad Sci U S A 99:7015–7020

[184] Varma R, Campi G, Yokosuka T, Saito T, Dustin ML (2006) T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25:117–127

[185] Vera J, Savoldo B, Vigouroux S, Biagi E, Pule M, Rossig C, Wu J, Heslop HE, Rooney CM, Brenner MK (2006) T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 108:3890–3897

[186] Vinuesa CG (2012) HIV and T follicular helper cells: a dangerous relationship. J Clin Invest 122:3059–3062

[187] Virgin HW, Wherry EJ, Ahmed R (2009) Redefining chronic viral infection. Cell 138:30–50

[188] Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S (2008) Functions of natural killer cells. Nat Immunol 9:503–510

[189] Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49

[190] Waggoner SN, Reighard SD, Gyurova IE, Cranert SA, Mahl SE, Karmele EP, McNally JP, Moran MT, Brooks TR, Yaqoob F (2016) Roles of natural killer cells in antiviral immunity. Curr Opin Virol 16:15–23

[191] Wang RF, Wang HY (2017) Immune targets and neoantigens for cancer immunotherapy and precision medicine. Cell Res 27:11–37

[192] Wang H, Cao F, De A, Cao Y, Contag C, Gambhir SS, Wu JC, Chen X (2009) Trafficking mesenchymal stem cell engraftment and differentiation in tumor-bearing mice by bioluminescence imaging. Stem Cells 27:1548–1558

[193] Ward J, Davis Z, DeHart J, Zimmerman E, Bosque A, Brunetta E, Mavilio D, Planelles V, Barker E (2009) HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog 5: e1000613

[194] Watzl C, Long EO (2010) Unit 11 19B Signal transduction during activation and inhibition of natural killer cells. Curr Protoc Immunol.

[195] Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492–499

[196] Yagita M, Huang CL, Umehara H, Matsuo Y, Tabata R, Miyake M, Konaka Y, Takatsuki K (2000) A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia 14:922–930

[197] Yang OO, Tran AC, Kalams SA, Johnson RP, Roberts MR, Walker BD (1997) Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor Tcells. Proc Natl Acad Sci U S A 94:11478–11483

[198] Yokoyama WM (2008) Mistaken notions about natural killer cells. Nat Immunol 9:481–485

[199] Zhang C, Burger MC, Jennewein L, Genssler S, Schonfeld K, Zeiner P, Hattingen E, Harter PN, Mittelbronn M, Tonn T (2016) ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst.

[200] Zhen A, Kamata M, Rezek V, Rick J, Levin B, Kasparian S, Chen IS, Yang OO, Zack JA, Kitchen SG (2015) HIV-specific immunity derived from chimeric antigen receptor-engineered stem cells. Mol Ther 23:1358–1367

[201] Zheng P, Bertolet G, Chen Y, Huang S, and Liu D (2015a) Superresolution imaging of the natural killer cell immunological synapse on a glass-supported planar lipid bilayer. J Vis Exp

[202] Zheng P, Noroski LM, Hanson IC, Chen Y, Lee ME, Huang Y, Zhu MX, Banerjee PP, Makedonas G, Orange JS (2015b) Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome. J Allergy Clin Immunol 135:1293–1302

RIGHTS & PERMISSIONS

2017 The Author(s) 2017. This article is an open access publication