Skip to main content
Top
Published in: Cancer Immunology, Immunotherapy 1/2014

01-01-2014 | Focussed Research Review

Advantages and clinical applications of natural killer cells in cancer immunotherapy

Authors: Erik Ames, William J. Murphy

Published in: Cancer Immunology, Immunotherapy | Issue 1/2014

Login to get access

Abstract

The past decade has witnessed a burgeoning of research and further insight into the biology and clinical applications of natural killer (NK) cells. Once thought to be simple innate cells important only as cytotoxic effector cells, our understanding of NK cells has grown to include memory-like responses, the guidance of adaptive responses, tissue repair, and a delicate paradigm for how NK cells become activated now termed “licensing” or “arming.” Although these cells were initially discovered and named for their spontaneous ability to kill tumor cells, manipulating NK cells in therapeutic settings has proved difficult and complex in part due to our emerging understanding of their biology. Therapies involving NK cells may either activate endogenous NK cells or involve transfers of exogenous cells by hematopoietic stem cell transplantation or adoptive cell therapy. Here, we review the basic biology of NK cells, highlighting characteristics which make NK cells particularly useful in cancer therapies. We also explore current treatment strategies that have been used for cancer as well as discuss potential future directions for the field.
Literature
3.
go back to reference Bennett M (1973) Prevention of marrow allograft rejection with radioactive strontium: evidence for marrow-dependent effector cells. J Immunol 110:510–516PubMed Bennett M (1973) Prevention of marrow allograft rejection with radioactive strontium: evidence for marrow-dependent effector cells. J Immunol 110:510–516PubMed
4.
go back to reference Herberman RB, Nunn ME, Lavrin DH (1975) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer 16:216–229PubMedCrossRef Herberman RB, Nunn ME, Lavrin DH (1975) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer 16:216–229PubMedCrossRef
5.
go back to reference Kiessling R, Klein E, Wigzell H (1975) “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. doi:10.1002/eji.1830050208 PubMedCrossRef Kiessling R, Klein E, Wigzell H (1975) “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. doi:10.​1002/​eji.​1830050208 PubMedCrossRef
6.
7.
go back to reference Magri G, Muntasell A, Romo N et al (2011) NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 117:848–856. doi:10.1182/blood-2010-08-301374 PubMedCrossRef Magri G, Muntasell A, Romo N et al (2011) NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 117:848–856. doi:10.​1182/​blood-2010-08-301374 PubMedCrossRef
8.
go back to reference Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5:1260–1265. doi:10.1038/ni1138 PubMedCrossRef Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5:1260–1265. doi:10.​1038/​ni1138 PubMedCrossRef
12.
go back to reference Sun K, Alvarez M, Ames E, Barao I, Chen M, Longo DL, Redelman D, Murphy WJ (2012) Mouse NK cell-mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing. Blood 119:1590–1598. doi:10.1182/blood-2011-08-374314 PubMedCrossRef Sun K, Alvarez M, Ames E, Barao I, Chen M, Longo DL, Redelman D, Murphy WJ (2012) Mouse NK cell-mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing. Blood 119:1590–1598. doi:10.​1182/​blood-2011-08-374314 PubMedCrossRef
18.
go back to reference Garg A, Barnes PF, Porgador A et al (2006) Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor. J Immunol 177:6192–6198PubMed Garg A, Barnes PF, Porgador A et al (2006) Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor. J Immunol 177:6192–6198PubMed
20.
go back to reference Hallett WH, Ames E, Motarjemi M, Barao I, Shanker A, Tamang DL, Sayers TJ, Hudig D, Murphy WJ (2008) Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol 180:163–170PubMed Hallett WH, Ames E, Motarjemi M, Barao I, Shanker A, Tamang DL, Sayers TJ, Hudig D, Murphy WJ (2008) Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J Immunol 180:163–170PubMed
21.
22.
go back to reference Curti A, Ruggeri L, D’Addio A et al (2011) Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118:3273–3279. doi:10.1182/blood-2011-01-329508 PubMedCrossRef Curti A, Ruggeri L, D’Addio A et al (2011) Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118:3273–3279. doi:10.​1182/​blood-2011-01-329508 PubMedCrossRef
24.
go back to reference Tallerico R, Todaro M, Di Franco S et al (2013) Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J Immunol 190:2381–2390. doi:10.4049/jimmunol.1201542 PubMedCrossRef Tallerico R, Todaro M, Di Franco S et al (2013) Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J Immunol 190:2381–2390. doi:10.​4049/​jimmunol.​1201542 PubMedCrossRef
25.
go back to reference Jewett A, Tseng HC, Arasteh A, Saadat S, Christensen RE, Cacalano NA (2012) Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells. Curr Drug Deliv 9:5–16PubMedCrossRef Jewett A, Tseng HC, Arasteh A, Saadat S, Christensen RE, Cacalano NA (2012) Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells. Curr Drug Deliv 9:5–16PubMedCrossRef
27.
go back to reference Rosenstein M, Ettinghausen SE, Rosenberg SA (1986) Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 137:1735–1742PubMed Rosenstein M, Ettinghausen SE, Rosenberg SA (1986) Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2. J Immunol 137:1735–1742PubMed
28.
go back to reference Meropol NJ, Porter M, Blumenson LE et al (1996) Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity. Clin Cancer Res 2:669–677PubMed Meropol NJ, Porter M, Blumenson LE et al (1996) Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity. Clin Cancer Res 2:669–677PubMed
30.
go back to reference Hallett WH, Ames E, Alvarez M, Barao I, Taylor PA, Blazar BR, Murphy WJ (2008) Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses. Biol Blood Marrow Transpl 14:1088–1099. doi:10.1016/j.bbmt.2008.08.001 CrossRef Hallett WH, Ames E, Alvarez M, Barao I, Taylor PA, Blazar BR, Murphy WJ (2008) Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses. Biol Blood Marrow Transpl 14:1088–1099. doi:10.​1016/​j.​bbmt.​2008.​08.​001 CrossRef
35.
go back to reference Yu J, Venstrom JM, Liu XR, Pring J, Hasan RS, O’Reilly RJ, Hsu KC (2009) Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood 113:3875–3884. doi:10.1182/blood-2008-09-177055 PubMedCrossRef Yu J, Venstrom JM, Liu XR, Pring J, Hasan RS, O’Reilly RJ, Hsu KC (2009) Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation. Blood 113:3875–3884. doi:10.​1182/​blood-2008-09-177055 PubMedCrossRef
37.
go back to reference Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, Beutel LD, De Leon C, Chico S (2004) Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother 27:398–404PubMedCrossRef Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, Beutel LD, De Leon C, Chico S (2004) Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother 27:398–404PubMedCrossRef
38.
go back to reference Burns LJ, Weisdorf DJ, DeFor TE et al (2003) IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transpl 32:177–186. doi:10.1038/sj.bmt.1704086 CrossRef Burns LJ, Weisdorf DJ, DeFor TE et al (2003) IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transpl 32:177–186. doi:10.​1038/​sj.​bmt.​1704086 CrossRef
40.
go back to reference Berg M, Lundqvist A, McCoy P Jr, Samsel L, Fan Y, Tawab A, Childs R (2009) Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 11:341–355. doi:10.1080/14653240902807034 PubMedCentralPubMedCrossRef Berg M, Lundqvist A, McCoy P Jr, Samsel L, Fan Y, Tawab A, Childs R (2009) Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 11:341–355. doi:10.​1080/​1465324090280703​4 PubMedCentralPubMedCrossRef
43.
go back to reference Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, Tonn T, Wels WS (2008) Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 57:411–423. doi:10.1007/s00262-007-0383-3 PubMedCrossRef Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, Tonn T, Wels WS (2008) Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 57:411–423. doi:10.​1007/​s00262-007-0383-3 PubMedCrossRef
44.
go back to reference 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 8:652–658PubMed 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 8:652–658PubMed
45.
go back to reference Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG (1999) Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther 10:1359–1373. doi:10.1089/10430349950018030 PubMedCrossRef Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG (1999) Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther 10:1359–1373. doi:10.​1089/​1043034995001803​0 PubMedCrossRef
46.
go back to reference 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. doi:10.1080/14653240802301872 PubMedCrossRef 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. doi:10.​1080/​1465324080230187​2 PubMedCrossRef
47.
go back to reference Cheng M, Ma J, Chen Y et al (2011) Establishment, characterization, and successful adaptive therapy against human tumors of NKG cell, a new human NK cell line. Cell Transpl 20:1731–1746. doi:10.3727/096368911X580536 CrossRef Cheng M, Ma J, Chen Y et al (2011) Establishment, characterization, and successful adaptive therapy against human tumors of NKG cell, a new human NK cell line. Cell Transpl 20:1731–1746. doi:10.​3727/​096368911X580536​ CrossRef
48.
50.
go back to reference Chikamatsu K, Reichert TE, Kashii Y, Saito T, Kawashiri S, Yamamoto E, Whiteside TL (1999) Immunotherapy with effector cells and IL-2 of lymph node metastases of human squamous-cell carcinoma of the head and neck established in nude mice. Int J Cancer∝ 82:532–537CrossRef Chikamatsu K, Reichert TE, Kashii Y, Saito T, Kawashiri S, Yamamoto E, Whiteside TL (1999) Immunotherapy with effector cells and IL-2 of lymph node metastases of human squamous-cell carcinoma of the head and neck established in nude mice. Int J Cancer∝ 82:532–537CrossRef
Metadata
Title
Advantages and clinical applications of natural killer cells in cancer immunotherapy
Authors
Erik Ames
William J. Murphy
Publication date
01-01-2014
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 1/2014
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-013-1469-8

Other articles of this Issue 1/2014

Cancer Immunology, Immunotherapy 1/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine