Top

Published in:

Open Access 01-10-2008 | Original Article

IL-21 induces in vivo immune activation of NK cells and CD8⁺ T cells in patients with metastatic melanoma and renal cell carcinoma

Authors: Klaus Stensgaard Frederiksen, Dorthe Lundsgaard, Jeremy A. Freeman, Steven D. Hughes, Thomas L. Holm, Birte K. Skrumsager, Andreas Petri, Lasse T. Hansen, Grant A. McArthur, Ian D. Davis, Kresten Skak

Published in: Cancer Immunology, Immunotherapy | Issue 10/2008

Abstract

Purpose

Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the effects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine.

Experimental design

Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 μg/kg using two planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily for five consecutive days followed by nine dose-free days (5 + 9). The following biomarkers were studied in peripheral blood mononuclear cells (PBMC) during treatment: phosphorylation of STAT3, alterations in the composition of leukocyte subsets, ex vivo cytotoxicity, expression of effector molecules in enriched CD8⁺ T cells and CD56⁺ NK cells by quantitative RT-PCR, and gene array profiling of CD8⁺ T cells.

Results

Effects of IL-21 were observed at all dose levels. In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods. In both CD8⁺ T cells and CD56⁺ NK cells we found up-regulation of perforin and granzyme B mRNA. In addition, full transcriptome analysis of CD8⁺ T cells displayed changes in several transcripts associated with increased cell cycle progression, cellular motility, and immune activation. Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo.

Conclusions

IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8⁺ T cell activation.

Available only for authorised users

Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (2001) Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol 167:1–5PubMed

Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang YT, Liu PY, Lyman GH, Morabito A (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634PubMed

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr., Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2001) Final version of the American joint committee on cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMed

Brady J, Hayakawa Y, Smyth MJ, Nutt SL (2004) IL-21 Induces the functional maturation of murine NK Cells. J Immunol 172:2048–2058PubMed

Chen A, Gaddipati S, Hong Y, Volkman DJ, Peerschke EI, Ghebrehiwet B (1994) Human T cells express specific binding sites for C1q. Role in T cell activation and proliferation. J Immunol 153:1430–1440PubMed

Cheng YS, Colonno RJ, Yin FH (1983) Interferon induction of fibroblast proteins with guanylate binding activity. J Biol Chem 258:7746–7750PubMed

Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, Mackay CR (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 173:68–78PubMed

Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ, Godfrey DI (2007) IL-21 Is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol 178:2827–2834PubMed

Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow J, Møller NPH, Skak K, Lundsgaard D, Frederiksen KS, Thygesen P, McArthur G (2007) An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 13:3630–3636PubMedCrossRef

10.

DeYoung KL, Ray ME, Su YA, Anzick SL, Johnstone RW, Trapani JA, Meltzer PS, Trent JM (1997) Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15:453–457PubMedCrossRef

11.

di Carlo E, de Totero D, Piazza T, Fabbi M, Ferrini S (2007) Role of IL-21 in immune-regulation and tumor immunotherapy. Cancer Immunol Immunother 56:1323–1334PubMedCrossRef

12.

Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, Leonard WJ, Lipsky PE (2005) IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol 175:7867–7879PubMed

13.

Fröhlich A, Marsland BJ, Sonderegger I, Kurrer M, Hodge MR, Harris NL, Kopf M (2007) IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. Blood 109:2023–2031PubMedCrossRef

14.

Gagnon J, Ramanathan S, Leblanc C, Ilangumaran S (2007) Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8+ T lymphocytes. Cell Signal 19:806–816PubMedCrossRef

15.

Good KL, Bryant VL, Tangye SG (2006) Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J Immunol 177:5236–5247PubMed

16.

Gotte M, Yip GW (2006) Heparanase, hyaluronan, and CD44 in cancers: A breast carcinoma perspective. Cancer Res 66:10233–10237PubMedCrossRef

17.

Guida M, Colucci G (2007) Immunotherapy for metastatic renal cell carcinoma: is it a therapeutic option yet? Ann Oncol 18:149–152CrossRef

18.

Hutloff A, Dittrich AM, Beler KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263–266PubMedCrossRef

19.

Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN-gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13:95–109PubMedCrossRef

20.

Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C (1993) Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science 261:466–469PubMedCrossRef

21.

Konforte D, Paige CJ (2006) Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells. J Immunol 177:8381–8392PubMed

22.

Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448:484–487PubMedCrossRef

23.

Laurence A, O’Shea JJ (2007) TH-17 differentiation: of mice and men. Nat Immunol 8:903–905PubMedCrossRef

24.

Leonard WJ, Spolski R (2005) Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 5:688–698PubMedCrossRef

25.

Li Y, Yee C (2008) IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111:229–235PubMedCrossRef

26.

Li Y, Bleakley M, Yee C (2005) IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J Immunol 175:2261–2269PubMed

27.

Ma HL, Whitters MJ, Konz RF, Senices M, Young DA, Grusby MJ, Collins M, Dunussi-Joannopoulos K (2003) IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma. J Immunol 171:608–615PubMed

28.

Martin M, Huguet J, Centelles JJ, Franco R (1995) Expression of ecto-adenosine deaminase and CD26 in human T cells triggered by the TCR-CD3 complex. Possible role of adenosine deaminase as costimulatory molecule. J Immunol 155:4630–4643PubMed

29.

McGuire MJ, Lipsky PE, Thiele DL (1993) Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I. J Biol Chem 268:2458–2467PubMed

30.

Moroz A, Eppolito C, Li Q, Tao J, Clegg CH, Shrikant PA (2004) IL-21 enhances and sustains CD8⁺ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 173:900–909PubMed

31.

Moser B, Wolf M, Walz A, Loetscher P (2004) Chemokines: multiple levels of leukocyte migration control. Trends immunol 25:75–84PubMedCrossRef

32.

Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116:221–234PubMedCrossRef

33.

Nanki T, Shimaoka T, Hayashida K, Taniguchi K, Yonehara S, Miyasaka N (2005) Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum 52:3004–3014PubMedCrossRef

34.

Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483PubMedCrossRef

35.

Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63PubMedCrossRef

36.

Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, Pallone F, Monteleone G (2007) IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 178:732–739PubMed

37.

Riker AI, Radfar S, Liu SH, Wang YX, Khong HT (2007) Immunotherapy of melanoma: a critical review of current concepts and future strategies. Expert Opin Biol Ther 7:345–358PubMedCrossRef

38.

Sandoval-Montes C, Santos-Argumedo L (2005) CD38 is expressed selectively during the activation of a subset of mature T cells with reduced proliferation but improved potential to produce cytokines. J Leukoc Biol 77:513–521PubMedCrossRef

39.

Schaerli P, Moser B (2005) Chemokines—control of primary and memory T-cell traffic. Immunol Res 31:57–74PubMedCrossRef

40.

Sondergaard H, Frederiksen KS, Thygesen P, Galsgaard ED, Skak K, Kristjansen PEG, Ødum N, Kragh M (2007) Interleukin 21 therapy increases the density of tumor infiltrating CD8+ T cells and inhibits the growth of syngeneic tumors. Cancer Immunol Immunother 56:1417–1428PubMedCrossRef

41.

Strengell M, Matikainen S, Siren J, Lehtonen A, Foster D, Julkunen I, Sareneva T (2003) IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-γ production in human NK and T Cells. J Immunol 170:5464PubMed

42.

Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S (2002) IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J Immunol 169:3600–3605PubMed

43.

Sutton VR, Waterhouse NJ, Browne KA, Sedelies K, Ciccone A, Anthony D, Koskinen A, Mullbacher A, Trapani JA (2007) Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis. J Cell Biol 176:425–433PubMedCrossRef

44.

Tanaka T, Camerini D, Seed B, Torimoto Y, Dang NH, Kameoka J, Dahlberg HN, Schlossman SF, Morimoto C (1992) Cloning and functional expression of the T cell activation antigen CD26. J Immunol 149:481–486PubMed

45.

Thompson JA, Curti BD, Redman BG, Weber JS, Agarwala SS, Sievers EL (2006) Interleukin-21 (IL-21): Tolerability and anti-tumor activity following two 5-day cycles in patients with stage IV melanoma (MM) or renal cell carcinoma (RCC). ASCO Abstract no. 2505

46.

Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM, Yu D, Domaschenz H, Whittle B, Lambe T, Roberts IS, Copley RR, Bell JI, Cornall RJ, Goodnow CC (2005) A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435:452–458PubMedCrossRef

47.

Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6:940–952PubMedCrossRef

48.

Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M, Grusby MJ (2002) Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J Exp Med 196:969–977PubMedCrossRef

49.

Zaman A, Cui Z, Foley JP, Zhao HJ, Grimm PC, DeLisser HM, Savani RC (2005) Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. Am J Respir Cell Mol Biol 33:447–454PubMedCrossRef

50.

Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, Berzofsky JA, Leonard WJ (2005) Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201:139–148PubMedCrossRef

51.

Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ (2007) The molecular basis of IL-21-mediated proliferation. Blood 109:4135–4142PubMedCrossRef

52.

Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967–974PubMedCrossRef

Title: IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma
Authors: Klaus Stensgaard Frederiksen
Dorthe Lundsgaard
Jeremy A. Freeman
Steven D. Hughes
Thomas L. Holm
Birte K. Skrumsager
Andreas Petri
Lasse T. Hansen
Grant A. McArthur
Ian D. Davis
Kresten Skak
Publication date: 01-10-2008
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 10/2008
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0479-4

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Experimental design

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2008

Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines

Translating immunity into cancer therapy: new findings from the first conference of the European Society for Cancer Immunology and Immunotherapy, an ESMO-EIS held in Athens, 15–17 November 2007

Dendritic cell vaccination and immune monitoring

Spontaneous immune responses to sporadic tumors: tumor-promoting, tumor-protective or both?

Gamma-IFN-inducible-lysosomal thiol reductase modulates acidic proteases and HLA class II antigen processing in melanoma

NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer