Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells.
BACKGROUND
Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting.


METHODS
In this study, we explored the beneficial effect of the immunostimulatory cytokine interleukin (IL)-15 on purified γδ T cells and its use as a stimulatory signal in the ex vivo expansion of γδ T cells for adoptive transfer. The expansion protocol was validated both with immune cells of healthy individuals and acute myeloid leukemia patients.


RESULTS
We report that the addition of IL-15 to γδ T cell cultures results in a more activated phenotype, a higher proliferative capacity, a more pronounced T helper 1 polarization, and an increased cytotoxic capacity of γδ T cells. Moreover γδ T cell expansion starting with peripheral blood mononuclear cells from healthy individuals and acute myeloid leukemia patients is boosted in the presence of IL-15, whereby the antitumor properties of the γδ T cells are strengthened as well.


CONCLUSIONS
Our results support the rationale to explore the use of IL-15 in clinical adoptive therapy protocols exploiting γδ T cells.
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium. heleen.vanacker@uantwerp.be.
Heleen H
HH
Van Acker
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
Sébastien
S
Anguille
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.
Yannick
Y
Willemen
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.
Johan M
JM
Van den Bergh
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
Zwi N
ZN
Berneman
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
Eva
E
Lion
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.|Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.|Center for Oncological Research (CORE), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Antwerp, Belgium.
Evelien L
EL
Smits
Laboratory of Experimental Hematology, Tumor Immunology Group (TIGR), Vaccine and Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.
Viggo F
VF
Van Tendeloo
Adoptive transfer; Expansion protocol; Gamma delta T cells; Interleukin-15; Leukemia
Am J Hematol. 2016 Jan;91(1):131-45
26598393
Cell. 2015 Apr 9;161(2):205-14
25860605
Nat Med. 2015 Aug;21(8):938-45
26193342
Trends Pharmacol Sci. 2012 Jan;33(1):35-41
22032984
J Clin Invest. 2016 Jan;126(1):318-34
26657860
Oncoimmunology. 2013 Feb 1;2(2):e23037
23524451
Cancer Res. 2007 Aug 1;67(15):7450-7
17671215
J Immunol Methods. 2009 Aug 15;347(1-2):12-8
19465023
Oncoimmunology. 2015 Apr 1;4(8):e1021538
26405575
Sci Transl Med. 2015 Dec 9;7(317):317ra198
26659572
Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14741-6
16203967
Oncoimmunology. 2013 Jan 1;2(1):e22892
23483102
Immunol Rev. 2014 Jan;257(1):250-63
24329802
Exp Hematol. 2014 Dec;42(12):1013-21.e1
25201755
Blood. 2011 Dec 22;118(26):6845-8
22067383
Scand J Immunol. 2015 Jun;81(6):459-68
25753378
Immunol Rev. 2008 Apr;222:357-68
18364014
Science. 2001 Oct 19;294(5542):605-9
11567106
Clin Cancer Res. 2008 Jul 1;14(13):4232-40
18594005
Nat Rev Immunol. 2015 Nov;15(11):683-91
26449179
Hum Immunol. 2006 Nov;67(11):863-73
17145366
Pharmacol Ther. 2016 Feb;158:24-40
26617219
J Immunother. 2008 Apr;31(3):313-23
18317356
Blood. 2012 Nov 8;120(19):3936-44
22966165
Blood. 2015 Apr 9;125(15):2349-58
25612623
Gene Ther. 2014 Apr;21(4):393-401
24572789
Cancer. 2015 Aug 15;121(16):2689-704
26095886
Blood. 2010 Jan 21;115(3):453-74
19880497
Blood. 2005 Jan 1;105(1):241-50
15345595
Nat Immunol. 2012 Dec;13(12):1187-95
23104097
Oncoimmunology. 2014 Nov 14;3(8):e953410
25960933
Blood. 2009 Jun 18;113(25):6361-71
19380870
Immunology. 2013 Apr;138(4):346-60
23181340
Eur J Cardiothorac Surg. 2010 May;37(5):1191-7
20137969
Cell Mol Life Sci. 2011 Jul;68(14):2443-52
21573785
Bone Marrow Transplant. 2007 Jun;39(12):751-7
17450185
Blood. 2013 Jan 24;121(4):573-84
23160470
J Immunol. 2007 Jan 15;178(2):757-64
17202336
Int J Cancer. 2016 May 1;138(9):2263-73
26662627
Nat Rev Immunol. 2006 Aug;6(8):595-601
16868550
Blood. 2014 Jun 12;123(24):3750-9
24782509
Br J Haematol. 2009 Jan;144(2):245-50
19016713
Front Immunol. 2014 Dec 11;5:636
25566249
Cell Mol Immunol. 2015 Nov;12(6):656-68
25864915
Nat Med. 2006 Mar;12(3):335-41
16474399
PLoS One. 2012;7(12):e51851
23284789
N Engl J Med. 1985 Dec 5;313(23):1485-92
3903508
J Immunol. 2010 Jul 1;185(1):126-33
20525896
Cell Mol Life Sci. 2011 Jul;68(14):2433-42
21547501
Leukemia. 2015 Apr;29(4):770-5
25005246
J Biol Regul Homeost Agents. 2014 Jan-Mar;28(1):81-90
24750794
Br J Cancer. 2011 Sep 6;105(6):778-86
21847128
Nat Med. 2011 Sep 18;17(10):1290-7
21926977
Cytokine Growth Factor Rev. 2015 Feb;26(1):15-24
25306466
Biol Blood Marrow Transplant. 2015 Jan;21(1):130-6
25445640
J Immunol. 2014 Mar 1;192(5):2237-43
24489097
Cytometry B Clin Cytom. 2006 Nov 15;70(6):379-90
16977635
Cancer Immunol Immunother. 2008 Nov;57(11):1599-609
18301889
Oncoimmunology. 2015 Apr 28;4(6):e1006088
26155411
J Clin Invest. 2016 Jun 1;126(6):2123-38
27111235
Oncoimmunology. 2014 Jan 1;3(1):e27572
24734216
Cytotherapy. 2013 Apr;15(4):481-91
23391461
J Clin Oncol. 2015 Jan 1;33(1):74-82
25403209