Top

Published in:

01-02-2017 | Original Article

Cytokine-induced killer cells hunt individual cancer cells in droves in a mouse model

Authors: Ji Sung Kim, Yong Guk Kim, Hong Kyung Lee, Eun Jae Park, Boyeong Kim, Jong Soon Kang, Heesoon Lee, Youngsoo Kim, Jin Tae Hong, Sang-Bae Han

Published in: Cancer Immunology, Immunotherapy | Issue 2/2017

Abstract

Cytotoxicity of cytokine-induced killer (CIK) cells depends mainly on their encounters with target cells, but how many CIK cells are required to kill an individual cancer cell is unknown. Here we used time-lapse imaging to quantify the critical effector cell number required to kill an individual target cell. CIK cells killed MHC-I-negative and MHC-I-positive cancer cells, but natural killer (NK) cells destroyed MHC-I-negative cells only. The average threshold number of CIK cells required to kill an individual cancer cell was 6.7 for MHC-I-negative cells and 6.9 for MHC-I-positive cells. That of NK cells was 2.4 for MHC-I-negative cells. Likely due to the higher threshold numbers, killing by CIK cells was delayed in comparison with NK cells: 40% of MHC-negative target cells were killed after 5 h when co-cultured with CIK cells and after 2 h with NK cells. Our data have implications for the rational design of CIK cell-based immunotherapy of cancer patients.

Available only for authorised users

Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348:62–68. doi:10.1126/science.aaa4967 CrossRefPubMed

Aranda F, Buque A, Bloy N, Castoldi F, Eggermont A, Cremer I, Fridman WH, Fucikova J, Galon J, Spisek R, Tartour E, Zitvogel L, Kroemer G, Galluzzi L (2015) Trial watch: adoptive cell transfer for oncological indications. Oncoimmunology 4:e1046673. doi:10.1080/2162402X.2015.1046673 CrossRefPubMedPubMedCentral

Schmeel FC, Schmeel LC, Gast SM, Schmidt-Wolf IG (2014) Adoptive immunotherapy strategies with cytokine-induced killer (CIK) cells in the treatment of hematological malignancies. Int J Mol Sci 15:14632–14648. doi:10.3390/ijms150814632 CrossRefPubMedPubMedCentral

Lee HK, Kim YG, Kim JS, Park EJ, Kim B, Park KH, Kang JS, Hong JT, Kim Y, Han SB (2016) Cytokine-induced killer cells interact with tumor lysate-pulsed dendritic cells via CCR5 signaling. Cancer Lett 378:142–149. doi:10.1016/j.canlet.2016.05.020 CrossRefPubMed

Schmidt-Wolf IG, Lefterova P, Johnston V, Scheffold C, Csipai M, Mehta BA, Tsuruo T, Huhn D, Negrin RS (1996) Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells. Cell Immunol 169:85–90. doi:10.1006/cimm.1996.0094 CrossRefPubMed

Zhang YS, Yuan FJ, Jia GF, Zhang JF, Hu LY, Huang L, Wang J, Dai ZQ (2005) CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R. World J Gastroenterol 11:3339–3345CrossRefPubMedPubMedCentral

Zhao Q, Zhang H, Li Y, Liu J, Hu X, Fan L (2010) Anti-tumor effects of CIK combined with oxaliplatin in human oxaliplatin-resistant gastric cancer cells in vivo and in vitro. J Exp Clin Cancer Res 29:118. doi:10.1186/1756-9966-29-118 CrossRefPubMedPubMedCentral

Nishimura R, Baker J, Beilhack A, Zeiser R, Olson JA, Sega EI, Karimi M, Negrin RS (2008) In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood 112:2563–2574. doi:10.1182/blood-2007-06-092817 CrossRefPubMedPubMedCentral

Dai C, Lin F, Geng R, Ge X, Tang W, Chang J, Wu Z, Liu X, Lin Y, Zhang Z, Li J (2016) Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer. Oncotarget 7:10332–10344. doi:10.18632/oncotarget.7243 PubMedPubMedCentral

10.

Chester C, Fritsch K, Kohrt HE (2015) Natural Killer Cell Immunomodulation: targeting Activating, Inhibitory, and Co-stimulatory Receptor Signaling for Cancer Immunotherapy. Front Immunol 6:601. doi:10.3389/fimmu.2015.00601 CrossRefPubMedPubMedCentral

11.

Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274. doi:10.1146/annurev.immunol.23.021704.115526 CrossRefPubMed

12.

Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84. doi:10.1111/j.1600-065X.2008.00660.x CrossRefPubMedPubMedCentral

13.

Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441. doi:10.1146/annurev-immunol-032712-095951 CrossRefPubMedPubMedCentral

14.

Mathew SO, Rao KK, Kim JR, Bambard ND, Mathew PA (2009) Functional role of human NK cell receptor 2B4 (CD244) isoforms. Eur J Immunol 39:1632–1641. doi:10.1002/eji.200838733 CrossRefPubMed

15.

Zhang Z, Wu N, Lu Y, Davidson D, Colonna M, Veillette A (2015) DNAM-1 controls NK cell activation via an ITT-like motif. J Exp Med 212:2165–2182. doi:10.1084/jem.20150792 CrossRefPubMedPubMedCentral

16.

Verneris MR, Karimi M, Baker J, Jayaswal A, Negrin RS (2004) Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8 + T cells. Blood 103:3065–3072. doi:10.1182/blood-2003-06-2125 CrossRefPubMed

17.

Zhang B, Zhao W, Li H, Chen Y, Tian H, Li L, Zhang L, Gao C, Zheng J (2016) Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155. Cancer Immunol Immunother 65:305–314. doi:10.1007/s00262-016-1799-4 CrossRefPubMed

18.

Pievani A, Borleri G, Pende D, Moretta L, Rambaldi A, Golay J, Introna M (2011) Dual-functional capability of CD3 + CD56 + CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. Blood 118:3301–3310. doi:10.1182/blood-2011-02-336321 CrossRefPubMed

19.

Kim YJ, Lim J, Kang JS, Kim HM, Lee HK, Ryu HS, Kim JY, Hong JT, Kim Y, Han SB (2010) Adoptive immunotherapy of human gastric cancer with ex vivo expanded T cells. Arch Pharm Res 33:1789–1795. doi:10.1007/s12272-010-1111-7 CrossRefPubMed

20.

Kim HS, Lee YJ, Lee HK, Kim JS, Park Y, Kang JS, Hwang BY, Hong JT, Kim Y, Han SB (2013) Bisabolangelone inhibits dendritic cell functions by blocking MAPK and NF-kappaB signaling. Food Chem Toxicol 59:26–33. doi:10.1016/j.fct.2013.05.013 CrossRefPubMed

21.

Weidmann E, Brieger J, Jahn B, Hoelzer D, Bergmann L, Mitrou PS (1995) Lactate dehydrogenase-release assay: a reliable, nonradioactive technique for analysis of cytotoxic lymphocyte-mediated lytic activity against blasts from acute myelocytic leukemia. Ann Hematol 70:153–158CrossRefPubMed

22.

Kim JY, Kim YJ, Kim JS, Ryu HS, Lee HK, Kang JS, Kim HM, Hong JT, Kim Y, Han SB (2011) Adjuvant effect of a natural TLR4 ligand on dendritic cell-based cancer immunotherapy. Cancer Lett 313:226–234. doi:10.1016/j.canlet.2011.09.009 CrossRefPubMed

23.

Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL (1991) Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 174:139–149CrossRefPubMed

24.

Linn YC, Lau SK, Liu BH, Ng LH, Yong HX, Hui KM (2009) Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology 126:423–435. doi:10.1111/j.1365-2567.2008.02910.x CrossRefPubMedPubMedCentral

25.

Sturmhofel K, Hammerling GJ (1990) Reconstitution of H-2 class I expression by gene transfection decreases susceptibility to natural killer cells of an EL4 class I loss variant. Eur J Immunol 20:171–177. doi:10.1002/eji.1830200125 CrossRefPubMed

26.

Maziarz RT, Mentzer SJ, Burakoff SJ, Faller DV (1990) Distinct effects of interferon-gamma and MHC class I surface antigen levels on resistance of the K562 tumor cell line to natural killer-mediated lysis. Cell Immunol 130:329–338CrossRefPubMed

27.

Maio M, Altomonte M, Tatake R, Zeff RA, Ferrone S (1991) Reduction in susceptibility to natural killer cell-mediated lysis of human FO-1 melanoma cells after induction of HLA class I antigen expression by transfection with B2 m gene. J Clin Invest 88:282–289. doi:10.1172/JCI115289 CrossRefPubMedPubMedCentral

28.

Ding X, Cao H, Chen X, Jin H, Liu Z, Wang G, Cai L, Li D, Niu C, Tian H, Yang L, Zhao Y, Li W, Cui J (2015) Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer. J Transl Med 13:158. doi:10.1186/s12967-015-0514-0 CrossRefPubMedPubMedCentral

29.

Niu C, Jin H, Li M, Xu J, Xu D, Hu J, He H, Li W, Cui J (2015) In vitro analysis of the proliferative capacity and cytotoxic effects of ex vivo induced natural killer cells, cytokine-induced killer cells, and gamma-delta T cells. BMC Immunol 16:61. doi:10.1186/s12865-015-0124-x CrossRefPubMedPubMedCentral

30.

Forslund E, Sohlberg E, Enqvist M, Olofsson PE, Malmberg KJ, Onfelt B (2015) Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57-KIR-NKG2A + NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57-KIR-NKG2A- NK Cells. J Immunol 195:3374–3381. doi:10.4049/jimmunol.1500171 CrossRefPubMed

31.

Olofsson PE, Forslund E, Vanherberghen B, Chechet K, Mickelin O, Ahlin AR, Everhorn T, Onfelt B (2014) Distinct Migration and Contact Dynamics of Resting and IL-2-Activated Human Natural Killer Cells. Front Immunol 5:80. doi:10.3389/fimmu.2014.00080 CrossRefPubMedPubMedCentral

32.

Vanherberghen B, Olofsson PE, Forslund E, Sternberg-Simon M, Khorshidi MA, Pacouret S, Guldevall K, Enqvist M, Malmberg KJ, Mehr R, Onfelt B (2013) Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood 121:1326–1334. doi:10.1182/blood-2012-06-439851 CrossRefPubMed

33.

Zhao X, Zhang Z, Li H, Huang J, Yang S, Xie T, Huang L, Yue D, Xu L, Wang L, Zhang W, Zhang Y (2015) Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. Cancer Lett 362:192–198. doi:10.1016/j.canlet.2015.03.043 CrossRefPubMed

34.

Wang S, Wang Z (2015) Efficacy and safety of dendritic cells co-cultured with cytokine-induced killer cells immunotherapy for non-small-cell lung cancer. Int Immunopharmacol 28:22–28. doi:10.1016/j.intimp.2015.05.021 CrossRefPubMed

35.

Chieregato K, Albiero E, Castegnaro S, Bernardi M, d’Amore ES, Zanon C, Madeo D, Rodeghiero F, Astori G (2012) A study on mutual interaction between cytokine induced killer cells and umbilical cord-derived mesenchymal cells: implication for their in vivo use. Blood Cells Mol Dis 49:159–165. doi:10.1016/j.bcmd.2012.05.009 CrossRefPubMed

36.

Li Y, Qu YH, Wu YF, Liu L, Lin XH, Huang K, Wei J (2015) Bone marrow mesenchymal stem cells suppressing activation of allogeneic cytokine-induced killer/natural killer cells either by direct or indirect interaction. Cell Biol Int 39:435–445. doi:10.1002/cbin.10404 CrossRefPubMed

37.

Li Y, Qu YH, Wu YF, Wang XP, Wei J, Huang WG, Zhou DH, Fang J, Huang K, Huang SL (2011) Bone marrow mesenchymal stem cells reduce the antitumor activity of cytokine-induced killer/natural killer cells in K562 NOD/SCID mice. Ann Hematol 90:873–885. doi:10.1007/s00277-011-1156-9 CrossRefPubMed

Title: Cytokine-induced killer cells hunt individual cancer cells in droves in a mouse model
Authors: Ji Sung Kim
Yong Guk Kim
Hong Kyung Lee
Eun Jae Park
Boyeong Kim
Jong Soon Kang
Heesoon Lee
Youngsoo Kim
Jin Tae Hong
Sang-Bae Han
Publication date: 01-02-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 2/2017
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-016-1934-2

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2017

Designing therapeutic cancer vaccines by mimicking viral infections

The fifteenth International Conference on Progress in Vaccination against Cancer (PIVAC-15), 6–8 October 2015, Tübingen, Germany: looking back on 15 years of progress

Rejection versus escape: the tumor MHC dilemma

Using natural products to promote caspase-8-dependent cancer cell death

Immunogenicity and efficacy of a rationally designed vaccine against vascular endothelial growth factor in mouse solid tumor models

Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies

Keynote webinar | Spotlight on antibody–drug conjugates in cancer