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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 9/2012

01-09-2012 | Original Article

IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients

Authors: B. Schilling, E. S. Halstead, P. Schuler, M. Harasymczuk, J. E. Egan, T. L. Whiteside

Published in: Cancer Immunology, Immunotherapy | Issue 9/2012

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Abstract

Background

IRX-2 is a primary biologic which has been used for the therapy of head and neck squamous cell cancer (HNSCC) with promising clinical results. Since NK-cell function is compromised in HNSCC patients, we tested the effects of IRX-2 on the restoration of human NK-cell functions in vitro.

Methods

Peripheral blood mononuclear cells (PBMC) were isolated from 23 HNSCC patients and 10 normal controls (NC). The NK-cell phenotype and functions were compared before and after culture ± IRX-2 or ± 50 IU/ml rhIL-2. Flow cytometry was used to study the NK-cell phenotype, cytotoxic activity and cytokine expression.

Results

Impaired NK-cell cytotoxicity in HNSCC patients was related to lower expression of NKG2D, NKp30 and NKp46 receptors (P < 0.05) and not to a decreased frequency of NK cells. Incubation of patients’ NK cells with IRX-2 up-regulated the percentage of receptor-positive NK cells (P < 0.05). It also up-regulated cytotoxicity of patients’ NK cells (P < 0.01) more effectively than rhIL-2 (P < 0.01). IRX-2, but not rhIL-2, protected NK cells from suppression mediated by TGF-β, and it restored (P < 0.05) expression of activating NK-cell receptors and NK-cell cytotoxicity suppressed by TGF-β. Expression of pSMAD was decreased in NK cells treated with IRX-2 but not in those treated with rhIL-2.

Conclusions

IRX-2 was more effective than IL-2 in enhancing NK-cell cytotoxicity and protecting NK-cell function of HNSCC patients in vitro, emphasizing the potential advantage of IRX-2 as a component of future therapies for HNSCC.
Appendix
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Literature
1.
Wolf GT, Fee WE Jr, Dolan RW, Moyer JS, Kaplan MJ, Spring PM, Suen J, Kenady DE, Newman JG, Carroll WR, Gillespie MB, Freeman SM, Baltzer L, Kirkley TD, Brandwein HJ, Hadden JW (2011) Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer. Head Neck 33:1666–1674PubMedCrossRef
2.
Freeman SM, Franco JL, Kenady DE, Baltzer L, Roth Z, Brandwein HJ, Hadden JW (2011) A phase 1 safety study of an IRX-2 regimen in patients with squamous cell carcinoma of the head and neck. Am J Clin Oncol 34:173–178PubMed
3.
Berinstein NL, Wolf GT, Naylor PH, Baltzer L, Egan JE, Brandwein HJ, Whiteside TL, Goldstein LC, El-Naggar A, Badoual C, Fridman WH, White JM, Hadden JW (2011) Increased lymphocyte infiltration in patients with head and neck cancer treated with the IRX-2 immunotherapy regimen. Cancer Immunol Immunother. doi:10.​1007/​s00262-011-1134-z
4.
Whiteside TL, Butterfiled LH, Naylor PH, Egan JE, Hadden JW, Baltzer L, Wolf GT, Berinstein NL (2011) A short course of neoadjuvant IRX-2 induces changes in peripheral blood lymphocyte subsets of patients with head and neck squamous cell carcinoma. Cancer Immunol Immunother. doi:10.​1007/​s00262-011-1136-x
5.
Hadden J, Verastegui E, Barrera JL, Kurman M, Meneses A, Zinser JW, de la Garza J, Hadden E (2003) A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck. Int Immunopharmacol 3:1073–1081PubMedCrossRef
6.
Czystowska M, Han J, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Signorelli K, Whiteside TL (2009) IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death Differ 16:708–718PubMedCrossRef
7.
Egan JE, Quadrini KJ, Santiago-Schwarz F, Hadden JW, Brandwein HJ, Signorelli KL (2007) IRX-2, a novel in vivo immunotherapeutic, induces maturation and activation of human dendritic cells in vitro. J Immunother 30:624–633PubMedCrossRef
8.
Trotta R, Col JD, Yu J, Ciarlariello D, Thomas B, Zhang X, Allard J 2nd, Wei M, Mao H, Byrd JC, Perrotti D, Caligiuri MA (2008) TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol 181:3784–3792PubMed
9.
10.
Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49PubMedCrossRef
11.
Gonzalez S, Groh V, Spies T (2006) Immunobiology of human NKG2D and its ligands. Curr Top Microbiol Immunol 298:121–138PubMedCrossRef
12.
Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, Moretta A, West R, Xu W, Vivier E, Levin SD (2009) The B7 family member B7–H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 206:1495–1503PubMedCrossRef
13.
Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91PubMedCrossRef
14.
Schantz SP, Shillitoe EJ, Brown B, Campbell B (1986) Natural killer cell activity and head and neck cancer: a clinical assessment. J Natl Cancer Inst 77:869–875PubMed
15.
Schantz SP, Goepfert H (1987) Multimodality therapy and distant metastases. The impact of natural killer cell activity. Arch Otolaryngol Head Neck Surg 113:1207–1213PubMedCrossRef
16.
Schantz SP, Dimery I, Lippman SM, Clayman GL, Pellegrino C, Morice R (1992) A phase II study of interleukin-2 and interferon-alpha in head and neck cancer. Invest New Drugs 10:217–223PubMedCrossRef
17.
Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M (2011) Blast-derived microvesicles in sera of acute myeloid leukemia patients suppresses NK cell function via membrane-associated TGF-{beta}1. Haematologica 96:1302–1309PubMedCrossRef
18.
Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172:7335–7340PubMed
19.
Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW Jr, Chatterjee SK (2005) Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol 175:5541–5550PubMed
20.
Rabinowich H, Vitolo D, Altarac S, Herberman RB, Whiteside TL (1992) Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. J Immunol 149:340–349PubMed
21.
Heo DS, Snyderman C, Gollin SM, Pan S, Walker E, Deka R, Barnes EL, Johnson JT, Herberman RB, Whiteside TL (1989) Biology, cytogenetics, and sensitivity to immunological effector cells of new head and neck squamous cell carcinoma lines. Cancer Res 49:5167–5175PubMed
22.
Kim GG, Donnenberg VS, Donnenberg AD, Gooding W, Whiteside TL (2007) A novel multiparametric flow cytometry-based cytotoxicity assay simultaneously immunophenotypes effector cells: comparisons to a 4 h 51Cr-release assay. J Immunol Meth 325:51–66CrossRef
23.
Whiteside TL, Bryant J, Day R, Herberman RB (1990) Natural killer cytotoxicity in the diagnosis of immune dysfunction: criteria for a reproducible assay. J Clin Lab Anal 4:102–114PubMedCrossRef
24.
Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR (2004) Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest 114:560–568PubMed
25.
Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A (2003) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 100:4120–4125PubMedCrossRef
26.
Wulff S, Pries R, Borngen K, Trenkly T, Wollenberg B (2009) Decreased levels of circulating regulatory NK cells in patients with head and neck cancer throughout all tumor stages. Anticancer Res 29:3053–3057PubMed
27.
28.
Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C, Moretta L, Moretta A (1997) p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med 186:1129–1136PubMedCrossRef
29.
Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, Marcenaro E, Accame L, Malaspina A, Biassoni R, Bottino C, Moretta L, Moretta A (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in a natural cytotoxicity mediated by human natural killer cells. J Exp Med 190:1505–1516PubMedCrossRef
30.
Garcia-Iglesias T, del Toro-Arreola A, Albarran-Somoza B, del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Duenas MG, Balderas-Pena LA, Bravo-Cuellar A, Ortiz-Lazareno PC, Daneri-Navarro A (2009) Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer 9:186. doi:10.​1186/​1471-2407-9-186 PubMedCrossRef
31.
Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M (2010) Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother 59:73–79PubMedCrossRef
32.
Chen XM, Xu XQ, Sun K, Hallett WH, Zhao JD, Zhang DL (2008) NKG2D ligands expression and NKG2D-mediated cytotoxicity in human laryngeal squamous carcinoma cells. Scand J Immunol 67:441–447PubMedCrossRef
33.
Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z (2008) Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol 180:7249–7258PubMed
34.
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 5:1260–1265PubMedCrossRef
35.
Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E (2005) Natural-killer cells and dendritic cells: “l’union fait la force”. Blood 106:2252–2258PubMedCrossRef
36.
Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, Aguila HL, Caligiuri MA (2002) In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 100:3633–3638PubMedCrossRef
37.
Czystowska M, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Whiteside TL (2011) Mechanisms of T-cell protection from death by IRX-2: a new immunotherapeutic. Cancer Immunol Immunother 60:495–506PubMedCrossRef
38.
Schilling B, Harasymczuk M, Schuler P, Egan JE, Whiteside TL (2011) IRX-2, a novel biologic, favors the expansion of T effector over T regulatory cells in a human tumor microenvironment model. J Mol Med. doi:10.​1007/​s00109-011-0813-8 PubMed
39.
Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584PubMedCrossRef
40.
Song H, Hur DY, Kim KE, Park H, Kim T, Kim CW, Bang S, Cho DH (2006) IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. Cell Immunol 242:39–45PubMedCrossRef
Metadata
Title
IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients
Authors
B. Schilling
E. S. Halstead
P. Schuler
M. Harasymczuk
J. E. Egan
T. L. Whiteside
Publication date
01-09-2012
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 9/2012
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-011-1197-x

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