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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells

Authors: Heleen H. Van Acker, Sébastien Anguille, Yannick Willemen, Johan M. Van den Bergh, Zwi N. Berneman, Eva Lion, Evelien L. Smits, Viggo F. Van Tendeloo

Published in: Journal of Hematology & Oncology | Issue 1/2016

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Abstract

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.
Literature
1.
Van Acker HH, Anguille S, Van Tendeloo VF, Lion E. Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy. Oncoimmunology. 2015;4:e1021538.CrossRefPubMedPubMedCentral
2.
Girardi M, Oppenheim DE, Steele CR, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science. 2001;294:605–9.CrossRefPubMed
3.
He W, Hao J, Dong S, et al. Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin. J Immunol. 2010;185:126–33.CrossRefPubMed
4.
Aswald JM, Wang XH, Aswald S, et al. Flow cytometric assessment of autologous gammadelta T cells in patients with acute myeloid leukemia: potential effector cells for immunotherapy? Cytometry B Clin Cytom. 2006;70:379–90.CrossRefPubMed
5.
Viey E, Lucas C, Romagne F, et al. Chemokine receptors expression and migration potential of tumor-infiltrating and peripheral-expanded Vgamma9Vdelta2 T cells from renal cell carcinoma patients. J Immunother. 2008;31:313–23.CrossRefPubMed
6.
7.
8.
Legut M, Cole DK, Sewell AK. The promise of gammadelta T cells and the gammadelta T cell receptor for cancer immunotherapy. Cell Mol Immunol. 2015;12:656–68.CrossRefPubMedPubMedCentral
9.
Kantarjian H. Acute myeloid leukemia—major progress over four decades and glimpses into the future. Am J Hematol. 2016;91:131–45.CrossRefPubMed
10.
Walter RB, Estey EH. Management of older or unfit patients with acute myeloid leukemia. Leukemia. 2015;29:770–5.CrossRefPubMed
11.
Grosso DA, Hess RC, Weiss MA. Immunotherapy in acute myeloid leukemia. Cancer. 2015;121:2689–704.CrossRefPubMed
12.
Minculescu L, Sengelov H. The role of gamma delta T cells in haematopoietic stem cell transplantation. Scand J Immunol. 2015;81:459–68.CrossRefPubMed
13.
Perko R, Kang G, Sunkara A, et al. Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia. Biol Blood Marrow Transplant. 2015;21:130–6.CrossRefPubMed
14.
Godder KT, Henslee-Downey PJ, Mehta J, et al. Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant. 2007;39:751–7.CrossRefPubMed
15.
Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.CrossRefPubMed
16.
Buccheri S, Guggino G, Caccamo N, et al. Efficacy and safety of gammadeltaT cell-based tumor immunotherapy: a meta-analysis. J Biol Regul Homeost Agents. 2014;28:81–90.PubMed
17.
Airoldi I, Bertaina A, Prigione I, et al. Gammadelta T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-alphabeta+/CD19+ lymphocytes. Blood. 2015;125:2349–58.CrossRefPubMedPubMedCentral
18.
19.
Fisher JP, Heuijerjans J, Yan M, et al. Gammadelta T cells for cancer immunotherapy: a systematic review of clinical trials. Oncoimmunology. 2014;3:e27572.CrossRefPubMedPubMedCentral
20.
Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205–14.CrossRefPubMed
21.
Silva-Santos B, Serre K, Norell H. Gammadelta T cells in cancer. Nat Rev Immunol. 2015;15:683–91.CrossRefPubMed
22.
Van Acker HH, Anguille S, Willemen Y, et al. Bisphosphonates for cancer treatment: mechanisms of action and lessons from clinical trials. Pharmacol Ther. 2016;158:24–40.CrossRefPubMed
23.
Correia DV, Lopes A, Silva-Santos B. Tumor cell recognition by gammadelta T lymphocytes: T-cell receptor vs. NK-cell receptors. Oncoimmunology. 2013;2:e22892.CrossRefPubMedPubMedCentral
24.
Roelofs AJ, Jauhiainen M, Monkkonen H, et al. Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol. 2009;144:245–50.CrossRefPubMedPubMedCentral
25.
Nicol AJ, Tokuyama H, Mattarollo SR, et al. Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours. Br J Cancer. 2011;105:778–86.CrossRefPubMedPubMedCentral
26.
Conlon KC, Lugli E, Welles HC, et al. 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;33:74–82.CrossRefPubMed
27.
28.
Ring AM, Lin JX, Feng D, et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol. 2012;13:1187–95.CrossRefPubMedPubMedCentral
29.
Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6:595–601.CrossRefPubMed
30.
Van den Bergh JM, Van Tendeloo VF, Smits EL. Interleukin-15: new kid on the block for antitumor combination therapy. Cytokine Growth Factor Rev. 2014;26:15–24.
31.
Morris JC, Ramlogan-Steel CA, Yu P, et al. Vaccination with tumor cells expressing IL-15 and IL-15Ralpha inhibits murine breast and prostate cancer. Gene Ther. 2014;21:393–401.CrossRefPubMedPubMedCentral
32.
Teague RM, Sather BD, Sacks JA, et al. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med. 2006;12:335–41.CrossRefPubMed
33.
Bennouna J, Bompas E, Neidhardt EM, et al. Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2008;57:1599–609.CrossRefPubMed
34.
Salot S, Bercegeay S, Dreno B, et al. Large scale expansion of Vgamma9Vdelta2 T lymphocytes from human peripheral blood mononuclear cells after a positive selection using MACS “TCR gamma/delta + T cell isolation kit”. J Immunol Methods. 2009;347:12–8.CrossRefPubMed
35.
Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485–92.CrossRefPubMed
36.
Oliveira G, Ruggiero E, Stanghellini MT, et al. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory. Sci Transl Med. 2015;7:317ra198.CrossRefPubMed
37.
38.
Turtle CJ, Hanafi LA, Berger C et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–138.
39.
Sneller MC, Kopp WC, Engelke KJ, et al. IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8+ T effector memory population in peripheral blood. Blood. 2011;118:6845–8.CrossRefPubMedPubMedCentral
40.
Do JS, Min B. IL-15 produced and trans-presented by DCs underlies homeostatic competition between CD8 and {gamma}{delta} T cells in vivo. Blood. 2009;113:6361–71.CrossRefPubMedPubMedCentral
41.
French JD, Roark CL, Born WK, O'Brien RL. {gamma}{delta} T cell homeostasis is established in competition with {alpha}{beta} T cells and NK cells. Proc Natl Acad Sci U S A. 2005;102:14741–6.CrossRefPubMedPubMedCentral
42.
Capietto AH, Martinet L, Fournie JJ. How tumors might withstand gammadelta T-cell attack. Cell Mol Life Sci. 2011;68:2433–42.CrossRefPubMed
43.
Izumi T, Kondo M, Takahashi T, et al. Ex vivo characterization of gammadelta T-cell repertoire in patients after adoptive transfer of Vgamma9Vdelta2 T cells expressing the interleukin-2 receptor beta-chain and the common gamma-chain. Cytotherapy. 2013;15:481–91.CrossRefPubMed
44.
Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci. 2012;33:35–41.CrossRefPubMed
45.
Nakajima J, Murakawa T, Fukami T, et al. A phase I study of adoptive immunotherapy for recurrent non-small-cell lung cancer patients with autologous gammadelta T cells. Eur J Cardiothorac Surg. 2010;37:1191–7.CrossRefPubMed
46.
Dieli F, Vermijlen D, Fulfaro F, et al. Targeting human {gamma}delta} T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res. 2007;67:7450–7.CrossRefPubMedPubMedCentral
47.
Powell Jr DJ, Dudley ME, Robbins PF, Rosenberg SA. Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood. 2005;105:241–50.CrossRefPubMed
48.
Klebanoff CA, Scott CD, Leonardi AJ, et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Invest. 2016;126:318–34.CrossRefPubMed
49.
Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123:3750–9.CrossRefPubMedPubMedCentral
50.
51.
Cieri N, Camisa B, Cocchiarella F, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013;121:573–84.CrossRefPubMed
52.
Alexander AA, Maniar A, Cummings JS, et al. Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma. Clin Cancer Res. 2008;14:4232–40.CrossRefPubMedPubMedCentral
53.
Kelly-Rogers J, Madrigal-Estebas L, O'Connor T, Doherty DG. Activation-induced expression of CD56 by T cells is associated with a reprogramming of cytolytic activity and cytokine secretion profile in vitro. Hum Immunol. 2006;67:863–73.CrossRefPubMed
54.
Valgardsdottir R, Capitanio C, Texido G, et al. Direct involvement of CD56 in cytokine-induced killer-mediated lysis of CD56+ hematopoietic target cells. Exp Hematol. 2014;42:1013–21. e1011.CrossRefPubMed
55.
Wagner S, Wittekindt C, Reuschenbach M et al. CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma. Int J Cancer. 2015;138:2263–73.
56.
57.
Gruenbacher G, Nussbaumer O, Gander H, et al. Stress-related and homeostatic cytokines regulate Vgamma9Vdelta2 T-cell surveillance of mevalonate metabolism. Oncoimmunology. 2014;3:e953410.CrossRefPubMedPubMedCentral
58.
Tel J, Smits EL, Anguille S, et al. Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities. Blood. 2012;120:3936–44.CrossRefPubMed
59.
Anguille S, Lion E, Tel J, et al. Interleukin-15-induced CD56(+) myeloid dendritic cells combine potent tumor antigen presentation with direct tumoricidal potential. PLoS One. 2012;7:e51851.CrossRefPubMedPubMedCentral
60.
Moser B, Eberl M. gammadelta T-APCs: a novel tool for immunotherapy? Cell Mol Life Sci. 2011;68:2443–52.CrossRefPubMed
61.
Nakazato K, Yamada H, Yajima T, et al. Enforced expression of Bcl-2 partially restores cell numbers but not functions of TCRgammadelta intestinal intraepithelial T lymphocytes in IL-15-deficient mice. J Immunol. 2007;178:757–64.CrossRefPubMed
62.
Cairo C, Sagnia B, Cappelli G, et al. Human cord blood gammadelta T cells expressing public Vgamma2 chains dominate the response to bisphosphonate plus interleukin-15. Immunology. 2013;138:346–60.CrossRefPubMedPubMedCentral
63.
Ribot JC, Ribeiro ST, Correia DV, et al. Human gammadelta thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. J Immunol. 2014;192:2237–43.CrossRefPubMed
Metadata
Title
Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells
Authors
Heleen H. Van Acker
Sébastien Anguille
Yannick Willemen
Johan M. Van den Bergh
Zwi N. Berneman
Eva Lion
Evelien L. Smits
Viggo F. Van Tendeloo
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0329-3

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