Cetuximab reconstitutes pro-inflammatory cytokine secretions and tumor-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumor spheroids

Frontiers in Immunology

Volumn 6, Issue NOV, 2015, Pages

  Klöss, Stephan ^a   Chambron, Nicole ^b   Gardlowski, Tanja ^a   Weil, Sandra ^c   Koch, Joachim ^c   Esser, Ruth ^a   Von Strandmann, Elke Pogge ^d   Morgan, Michael A ^a   Arseniev, Lubomir ^a   Seitz, Oliver ^b   Köhl, Ulrike ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

^b Klinikum Hanau GmbH   (Germany)

^c INSTITUTE FOR TUMOR BIOLOGY AND EXPERIMENTAL THERAPY   (Germany)

^d UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

Author keywords

ADCC; Cetuximab activated NK cells; HNSCC tumor spheroids; Soluble MICA; TGF 1

Indexed keywords

CD16 ANTIGEN; CD3 ANTIGEN; CD56 ANTIGEN; CD9 ANTIGEN; CETUXIMAB; CYTOKINE; EPIDERMAL GROWTH FACTOR RECEPTOR; GAMMA INTERFERON; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2; NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 1; NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 2; NATURAL CYTOTOXICITY TRIGGERING RECEPTOR 3; NATURAL KILLER CELL RECEPTOR NKG2D; PEPTIDE; SOLUBLE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I CHAIN RELATED PEPTIDE A; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG;

ADULT; AGED; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ARTICLE; BIOASSAY; BLOCKING ASSAY; CELL INFILTRATION; CELL SUSPENSION; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOKINE RELEASE; CYTOTOXICITY ASSAY; DISEASE SURVEILLANCE; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; FLOW CYTOMETRY; FLUORESCENCE MICROSCOPY; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IMMUNOMAGNETIC SEPARATION; MAJOR HISTOCOMPATIBILITY COMPLEX; MALE; NATURAL KILLER CELL; NATURAL KILLER GROUP 2 MEMBER D; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; TIME-LAPSE VIDEO MICROSCOPY; TUMOR IMMUNITY; TUMOR SPHEROID;

EID: 84949565671     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2015.00543     Document Type: Article

References (80)

1. Trinchieri G. Biology of natural killer cells. Adv Immunol (1989) 47:187-376. doi: 10.1016/S0065-2776(08)60664-1.
2. Farag SS, Caligiuri MA. Human natural killer cell development and biology. Blood Rev (2006) 20(3):123-37. doi:10.1016/j.blre.2005.10.001.
3. Trinchieri G. Natural killer cells wear different hats: effector cells of innate resistance and regulatory cells of adaptive immunity and of hematopoiesis. Semin Immunol (1995) 7(2):83-8. doi:10.1006/smim.1995.0012.
4. Zwirner NW, Fuertes MB, Girart MV, Domaica CI, Rossi LE. Cytokine-driven regulation of NK cell functions in tumor immunity: role of the MICA-NKG2D system. Cytokine Growth Factor Rev (2007) 18(1-2):159-70. doi:10.1016/j.cytogfr.2007.01.013.
5. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural-killer cells and dendritic cells: "l'union fait la force". Blood (2005) 106(7):2252-8. doi:10.1182/blood-2005-03-1154.
6. Lee SC, Srivastava RM, Lopez-Albaitero A, Ferrone S, Ferris RL. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res (2011) 50(2-3):248-54. doi:10.1007/s12026-011-8231-0.
7. Lanier LL. Missing self, NK cells, and the white album. J Immunol (2005) 174(11):6565. doi:10.4049/jimmunol.174.11.6565.
8. Lanier LL. NK cell recognition. Annu Rev Immunol (2005) 23:225-74. doi:10.1146/annurev.immunol.23.021704.115526.
9. Coudert JD, Held W. The role of the NKG2D receptor for tumor immunity. Semin Cancer Biol (2006) 16(5):333-43. doi:10.1016/j.semcancer.2006.07.008.
10. Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood (2003) 102(4):1389-96. doi:10.1182/blood-2003-01-0019.
11. Huenecke S, Zimmermann SY, Kloess S, Esser R, Brinkmann A, Tramsen L, et al. IL-2-driven regulation of NK cell receptors with regard to the distribution of CD16+ and CD16-subpopulations and in vivo influence after haploidentical NK cell infusion. J Immunother (2010) 33(2):200-10. doi:10.1097/CJI.0b013e3181bb46f7.
12. Bryceson YT, Ljunggren HG. Tumor cell recognition by the NK cell activating receptor NKG2D. Eur J Immunol (2008) 38(11):2957-61. doi:10.1002/eji.200838833.
13. Franchi A, Santucci M, Masini E, Sardi I, Paglierani M, Gallo O. Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck. Cancer (2002) 95(9):1902-10. doi:10.1002/cncr.10916.
14. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature (2002) 419(6908):734-8. doi:10.1038/nature01112.
15. Holdenrieder S, Stieber P, PeterfiA, Nagel D, Steinle A, Salih HR. Soluble MICB in malignant diseases: analysis of diagnostic significance and correlation with soluble MICA. Cancer Immunol Immunother (2006) 55(12):1584-9. doi:10.1007/s00262-006-0167-1.
16. Holdenrieder S, Stieber P, PeterfiA, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases. Int J Cancer (2006) 118(3):684-7. doi:10.1002/ijc.21382.
17. Shibuya K, Mathers CD, Boschi-Pinto C, Lopez AD, Murray CJ. Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000. BMC Cancer (2002) 2:37. doi:10.1186/1471-2407-2-37.
18. Ragin CC, Modugno F, Gollin SM. The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J Dent Res (2007) 86(2):104-14. doi:10.1177/154405910708600202.
19. Duray A, Demoulin S, Hubert P, Delvenne P, Saussez S. Immune suppression in head and neck cancers: a review. Clin Dev Immunol (2010) 2010:701657. doi:10.1155/2010/701657.
20. Dasgupta S, Bhattacharya-Chatterjee M, O'Malley BW Jr, Chatterjee SK. 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 (2005) 175(8):5541-50. doi:10.4049/jimmunol.175.8.5541.
21. Tamaki S, Sanefuzi N, Kawakami M, Aoki K, Imai Y, Yamanaka Y, et al. Association between soluble MICA levels and disease stage IV oral squamous cell carcinoma in Japanese patients. Hum Immunol (2008) 69(2):88-93. doi:10.1016/j.humimm.2008.01.010.
22. Kloess S, et al. Increased sMICA and TGF-β1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells. Oncoimmunology (2015) 4(11):e1055993. doi:10.1080/2162402X.2015.1055993.
23. Tamaki S, Kawakami M, Ishitani A, Kawashima W, Kasuda S, Yamanaka Y, et al. Soluble MICB serum levels correlate with disease stage and survival rate in patients with oral squamous cell carcinoma. Anticancer Res (2010) 30(10):4097-101.
24. Roskoski R Jr. ErbB/HER protein-tyrosine kinases: structures and small molecule inhibitors. Pharmacol Res (2014) 87:42-59. doi:10.1016/j.phrs.2014.06.001.
25. Roskoski R Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res (2014) 79:34-74. doi:10.1016/j.phrs.2013.11.002.
26. Montemurro F, Scaltriti M. Biomarkers of drugs targeting HER-family signalling in cancer. J Pathol (2014) 232(2):219-29. doi:10.1002/path.4269.
27. Zuo JH, Zhu W, Li MY, Li XH, Yi H, Zeng GQ, et al. Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin. J Cell Biochem (2011) 112(9):2508-17. doi:10.1002/jcb.23175.
28. Lee CM, Tannock IF. The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors. BMC Cancer (2010) 10:255. doi:10.1186/1471-2407-10-255.
29. Hong KW, Kim CG, Lee SH, Chang KH, Shin YW, Ryoo KH, et al. A novel anti-EGFR monoclonal antibody inhibiting tumor cell growth by recognizing different epitopes from cetuximab. J Biotechnol (2010) 145(1):84-91. doi:10.1016/j.jbiotec.2009.09.023.
30. Campoli M, Ferris R, Ferrone S, Wang X. Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies. Clin Cancer Res (2010) 16(1):11-20. doi:10.1158/1078-0432.CCR-09-2345.
31. Ferris RL, Jaffee EM, Ferrone S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol (2010) 28(28):4390-9. doi:10.1200/JCO.2009.27.6360.
32. William WN Jr, Kim ES, Herbst RS. Cetuximab therapy for patients with advanced squamous cell carcinomas of the head and neck. Nat Clin Pract Oncol (2009) 6(3):132-3. doi:10.1038/ncponc1321.
33. Blumenschein GR Jr, Paulus R, Curran WJ, Robert F, Fossella F, Werner-Wasik M, et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol (2011) 29(17):2312-8. doi:10.1200/JCO.2010.31.7875.
34. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol (2006) 24(30):4914-21. doi:10.1200/JCO.2006.06.7595.
35. Bonner JA, Keene KS. Is cetuximab active in patients with cisplatin-refractory squamous cell carcinoma of the head and neck? Nat Clin Pract Oncol (2007) 4(12):690-1. doi:10.1038/ncponc0962.
36. Taylor RJ, Chan SL, Wood A, Voskens CJ, Wolf JS, Lin W, et al. FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother (2009) 58(7):997-1006. doi:10.1007/s00262-008-0613-3.
37. López-Albaitero A, Lee SC, Morgan S, Grandis JR, Gooding WE, Ferrone S, et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother (2009) 58(11):1853-64. doi:10.1007/s00262-009-0697-4.
38. López-Albaitero A, Nayak JV, Ogino T, Machandia A, Gooding W, DeLeo AB, et al. Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol (2006) 176(6):3402-9. doi:10.4049/jimmunol.176.6.3402.
39. Carrega P, Morandi B, Costa R, Frumento G, Forte G, Altavilla G, et al. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells. Cancer (2008) 112(4):863-75. doi:10.1002/cncr.23239.
40. Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun (2007) 7:4.
41. Bruno A, Ferlazzo G, Albini A, Noonan DM. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J Natl Cancer Inst (2014) 106(8):dju200. doi:10.1093/jnci/dju200.
42. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol (2014) 44(6):1582-92. doi:10.1002/eji.201344272.
43. Maréchal R, De Schutter J, Nagy N, Demetter P, Lemmers A, Devière J, et al. Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients. BMC Cancer (2010) 10:340. doi:10.1186/1471-2407-10-340.
44. Huenecke S, Behl M, Fadler C, Zimmermann SY, Bochennek K, Tramsen L, et al. Age-matched lymphocyte subpopulation reference values in childhood and adolescence: application of exponential regression analysis. Eur J Haematol (2008) 80(6):532-9. doi:10.1111/j.1600-0609.2008.01052.x.
45. Rheinwald JG, Beckett MA. Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell (1980) 22(2 Pt 2):629-32. doi:10.1016/0092-8674(80)90373-6.
46. Rheinwald JG, Beckett MA. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from human squamous cell carcinomas. Cancer Res (1981) 41(5):1657-63.
47. Kloess S, Huenecke S, Piechulek D, Esser R, Koch J, Brehm C, et al. IL-2-activated haploidentical NK cells restore NKG2D-mediated NK-cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA. Eur J Immunol (2010) 40(11):3255-67. doi:10.1002/eji.201040568.
48. Klöss S, Bochennek K, Huenecke S, Zimmermann SY, Kuçi S, Müller T, et al. A novel five-colour flow cytometric assay to determine NK cell cytotoxicity against neuroblastoma and other adherent tumour cells. J Immunol Methods (2007) 325(1-2):140-7. doi:10.1016/j.jim.2007.06.013.
49. Zimmermann SY, Esser R, Rohrbach E, Klingebiel T, Koehl U. A novel four-colour flow cytometric assay to determine natural killer cell or T-cell-mediated cellular cytotoxicity against leukaemic cells in peripheral or bone marrow specimens containing greater than 20% of normal cells. J Immunol Methods (2005) 296(1-2):63-76. doi:10.1016/j.jim.2004.10.014.
50. Comans-Bitter WM, de Groot R, van den Beemd R, Neijens HJ, Hop WC, Groeneveld K, et al. Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr (1997) 130(3):388-93.
51. Li H, Wawrose JS, Gooding WE, Garraway LA, Lui VW, Peyser ND, et al. Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res (2014) 12(4):571-82. doi:10.1158/1541-7786.MCR-13-0396.
52. Marten A, von Lilienfeld-Toal M, Buchler MW, Schmidt J. Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing gammadelta T cell cytotoxicity. Int J Cancer (2006) 119(10):2359-65. doi:10.1002/ijc.22186.
53. Roda JM, Joshi T, Butchar JP, McAlees JW, Lehman A, Tridandapani S, et al. The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Clin Cancer Res (2007) 13(21):6419-28. doi:10.1158/1078-0432.CCR-07-0865.
54. Bose A, Chakraborty T, Chakraborty K, Pal S, Baral R. Dysregulation in immune functions is reflected in tumor cell cytotoxicity by peripheral blood mononuclear cells from head and neck squamous cell carcinoma patients. Cancer Immun (2008) 8:10.
55. Walzer T, Dalod M, Vivier E, Zitvogel L. Natural killer cell-dendritic cell crosstalk in the initiation of immune responses. Expert Opin Biol Ther (2005) 5(Suppl 1):S49-59. doi:10.1517/14712598.5.1.S49.
56. WulffS, Pries R, Borngen K, Trenkle T, Wollenberg B. Decreased levels of circulating regulatory NK cells in patients with head and neck cancer throughout all tumor stages. Anticancer Res (2009) 29(8):3053-7.
57. Rossi LE, Avila DE, Spallanzani RG, Ziblat A, Fuertes MB, Lapyckyj L, et al. Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J Leukoc Biol (2012) 91(2):321-31. doi:10.1189/jlb.0711339.
58. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res (2013) 73(6):1733-41. doi:10.1158/0008-5472.CAN-12-2384.
59. Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood (2010) 116(13):2286-94. doi:10.1182/blood-2010-02-271874.
60. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res (2011) 71(16):5412-22. doi:10.1158/0008-5472.CAN-10-4179.
61. Mamessier E, Sylvain A, Bertucci F, Castellano R, Finetti P, Houvenaeghel G, et al. Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition. Cancer Res (2011) 71(21):6621-32. doi:10.1158/0008-5472.CAN-11-0792.
62. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol (2008) 180(11):7249-58. doi:10.4049/jimmunol.180.11.7249.
63. Crane CA, Han SJ, Barry JJ, Ahn BJ, Lanier LL, Parsa AT. TGF-beta downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro Oncol (2010) 12(1):7-13. doi:10.1093/neuonc/nop009.
64. Cerboni C, Ardolino M, Santoni A, Zingoni A. Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells. Blood (2009) 113(13):2955-64. doi:10.1182/blood-2008-06-165944.
65. Roberti MP, Rocca YS, Amat M, Pampena MB, Loza J, Coló F, et al. IL-2-or IL-15-activated NK cells enhance cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients. Breast Cancer Res Treat (2012) 136(3):659-71. doi:10.1007/s10549-012-2287-y.
66. Varilla V, Atienza J, Dasanu CA. Immune alterations and immunotherapy prospects in head and neck cancer. Expert Opin Biol Ther (2013) 13(9):1241-56. doi:10.1517/14712598.2013.810716.
67. Xia W, Lau YK, Zhang HZ, Xiao FY, Johnston DA, Liu AR, et al. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin Cancer Res (1999) 5(12):4164-74.
68. Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res (2007) 13(5):1552-61. doi:10.1158/1078-0432.CCR-06-1726.
69. Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie HB, Davidson HC, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res (2013) 19(7):1858-72. doi:10.1158/1078-0432.CCR-12-2426.
70. Brehm C, Huenecke S, Esser R, Kloess S, Quaiser A, Betz S, et al. Interleukin-2-stimulated natural killer cells are less susceptible to mycophenolate mofetil than non-activated NK cells: possible consequences for immunotherapy. Cancer Immunol Immunother (2014) 63(8):821-33. doi:10.1007/s00262-014-1556-5.
71. Giannattasio A, Weil S, Kloess S, Ansari N, Stelzer EH, Cerwenka A, et al. Cytotoxicity and infiltration of human NK cells in in vivo-like tumor spheroids. BMC Cancer (2015) 15:351. doi:10.1186/s12885-015-1321-y.
72. Hoh A, Dewerth A, Vogt F, Wenz J, Baeuerle PA, Warmann SW, et al. The activity of gammadelta T cells against paediatric liver tumour cells and spheroids in cell culture. Liver Int (2013) 33(1):127-36. doi:10.1111/liv.12011.
73. Holmes TD, El-Sherbiny YM, Davison A, Clough SL, Blair GE, Cook GP. A human NK cell activation/inhibition threshold allows small changes in the target cell surface phenotype to dramatically alter susceptibility to NK cells. J Immunol (2011) 186(3):1538-45. doi:10.4049/jimmunol.1000951.
74. de Boer E, Warram JM, Tucker MD, Hartman YE, Moore LS, de Jong JS, et al. In vivo fluorescence immunohistochemistry: localization of fluorescently labeled cetuximab in squamous cell carcinomas. Sci Rep (2015) 5:10169. doi:10.1038/srep10169.
75. Peria M, Donnadieu J, Racz C, Ikoli JF, Galmiche A, Chauffert B, et al. Evaluation of individual sensitivity of head and neck squamous cell carcinoma to cetuximab by short-term culture of tumor slices. Head Neck (2015). doi:10.1002/hed.24126.
76. Boeckx C, Van den Bossche J, De Pauw I, Peeters M, Lardon F, Baay M, et al. The hypoxic tumor microenvironment and drug resistance against EGFR inhibitors: preclinical study in cetuximab-sensitive head and neck squamous cell carcinoma cell lines. BMC Res Notes (2015) 8:203. doi:10.1186/s13104-015-1197-6.
77. Wang WM, Zhao ZL, Ma SR, Yu GT, Liu B, Zhang L, et al. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1alpha and Notch1 in head neck squamous cell carcinoma. PLoS One (2015) 10(2):e0119723. doi:10.1371/journal.pone.0119723.
78. Baragano Raneros A, Suarez-Alvarez B, Lopez-Larrea C. Secretory pathways generating immunosuppressive NKG2D ligands: new targets for therapeutic intervention. Oncoimmunology (2014) 3:e28497. doi:10.4161/onci.28497.
79. Koehl U, Brehm C, Huenecke S, Zimmermann SY, Kloess S, Bremm M, et al. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Front Oncol (2013) 3:118. doi:10.3389/fonc.2013.00118.
80. Stern M, Passweg JR, Meyer-Monard S, Esser R, Tonn T, Soerensen J, et al. Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers. Bone Marrow Transplant (2013) 48(3):433-8. doi:10.1038/bmt.2012.162.