Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 9/2006

01-09-2006 | Original Article

Inhibition of nuclear factor kappa B (NFκB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation

Authors: Anahid Jewett, Nicholas A. Cacalano, Antonia Teruel, Marcela Romero, Marjan Rashedi, Meiying Wang, Hiromi Nakamura

Published in: Cancer Immunology, Immunotherapy | Issue 9/2006

Login to get access

Abstract

The aim of this study is to identify candidate factors which may be responsible for the functional inactivation and depletion of NK cells by tumor cells. Inhibition of NFκB activity by an IκB super-repressor in HEp2 cells, a cell line commonly used as an oral tumor model, blocked tumor-induced NK cell death, and increased the function of NK cells significantly. Increased expression of CD69 early activation antigen on NK cells as well as augmented proliferation and secretion of IFN-γ by NK cells were observed when these cells were co-incubated with IκB super-repressor transfected HEp2 cells (HEp2-IκB(S32AS36A)). More importantly, the secretion of IL-6 was significantly inhibited when NK cells were co-cultured with HEp2-IκB(S32AS36A) cells. In addition, the survival and function of cytotoxic effector cells remained significantly elevated in the presence of IFN-γ-treated HEp2-IκB(S32AS36A) cells when compared to either untreated or IFN-γ-treated vector-alone transfected HEp2 cells. Similar findings to those obtained using purified peripheral blood NK cells were also observed when non-fractionated peripheral blood mononuclear cells were used in the co-cultures of immune effectors with HEp2 cell transfectants. Addition of recombinant human IL-6 to the co-cultures of immune effectors with the NFκB knockdown HEp2 tumor cells substantially decreased the levels of secreted IFN-γ. Thus, the results presented in this paper suggest that the inhibition of NFκB function in oral tumors may serve to activate and expand the function and numbers of NK cells. Moreover, NFκB-mediated increase in IL-6 secretion by oral tumors may in part be responsible for the observed inactivation and death of the immune effectors.
Literature
1.
Castiglione F, Destefanis M, Marenco D, Gosso P, Manera G, Porcile G. (1996) The mammographic screening project in 2 local health units of Piemonte. Epidemiol Prev 20:157PubMed
2.
Veltri RW, Rodman SM, Maxim PE, Baseler MW, Sprinkle PM (1986) Immune complexes, serum proteins, cell-mediated immunity, and immune regulation in patients with squamous cell carcinoma of the head and neck. Cancer 57:2295PubMedCrossRef
3.
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 77:869PubMed
4.
Marrogi AJ, Munshi A, Merogi AJ, Ohadike Y, El-Habashi A, Marrogi OL, Freeman SM (1997) Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 74:492PubMedCrossRef
5.
Camp BJ, Dyhrman ST, Memoli VA, Mott LA, Barth RJ Jr (1996) In situ cytokine production by breast cancer tumor-infiltrating lymphocytes. Ann Surg Oncol 3:176CrossRefPubMed
6.
Hartveit F (1998) Breast cancer: poor short-term prognosis in cases with moderate lymphocyte infiltration at the tumour edge: a preliminary report. Oncol Rep 5:423PubMed
7.
Gimmi CD, Morrison BW, Mainprice BA, Gribben JG, Boussiotis VA, Freeman GJ, Park SY, Watanabe M, Gong J, Hayes DF, Kufe DW, Nadler LM (1996) Breast cancer-associated antigen, DF3/MUC1, induces apoptosis of activated human T cells. Nat Med 2:1367CrossRefPubMed
8.
Kolenko V, Wang Q, Riedy MC, O’Shea J, Ritz J, Cathcart MK, Rayman P, Tubbs R, Edinger M, Novick A, Bukowski R, Finke J (1997) Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas. J Immunol 159:3057PubMed
9.
Mulder WM, Bloemena E, Stukart MJ, Kummer JA, Wagstaff J, Scheper RJ (1997) T cell receptor-zeta and granzyme B expression in mononuclear cell infiltrates in normal colon mucosa and colon carcinoma. Gut 40:113PubMed
10.
Hayry P, Totterman. TH (1978) Cytological and functional analysis of inflammatory infiltrates in human malignant tumors I Composition of the inflammatory infiltrates. Eur J Immunol 8:866PubMedCrossRef
11.
Miescher S, Stoeck M, Qiao L, Barras C, Barrelet L, von Fliedner V (1988) Preferential clonogenic deficit of CD8-positive T-lymphocytes infiltrating human solid tumors. Cancer Res 48:6992PubMed
12.
Qin J, Han B, Pang J (1997) The relationship between TIL from human primary hepatic carcinoma and prognosis. Zhonghua Yi Xue Za Zhi 77:167PubMed
13.
Han X, Papadopoulos AJ, Ruparelia V, Devaja O, Raju KS (1997) Tumor lymphocytes in patients with advanced ovarian cancer: changes during in vitro culture and implications for immunotherapy. Gynecol Oncol 65:391CrossRefPubMed
14.
Itoh K, Tilden AB, Balch CM (1986) Interleukin 2 activation of cytotoxic T-lymphocytes infiltrating into human metastatic melanomas. Cancer Res 46:3011PubMed
15.
Jewett A, Bonavida B (1996) Target-induced inactivation and cell death by apoptosis in a subset of human NK cells. J Immunol 156:907PubMed
16.
17.
18.
Andela VB, Schwarz EM, Puzas JE, O’Keefe RJ, Rosier RN (2000) Tumor metastasis and the reciprocal regulation of prometastatic and antimetastatic factors by nuclear factor kappaB. Cancer Res 60:6557PubMed
19.
Mukhopadhyay T, Roth JA, Maxwell SA (1995) Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma. Oncogene 11:999PubMed
20.
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr (1997) Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629PubMed
21.
Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ (1999) The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5:119PubMed
22.
Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, Nakamura K, Yamanaka T, Uchiyama A, Tanaka M, Katano M (2001) Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 7:4136PubMed
23.
McNulty SE, Tohidian NB, Meyskens FL Jr. 2001. RelA, p50 and inhibitor of kappa B alpha are elevated in human metastatic melanoma cells and respond aberrantly to ultraviolet light B. Pigment Cell Res 14:456CrossRefPubMed
24.
Nakayama H, Ikebe T, Beppu M, Shirasuna K (2001) High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer 92:3037CrossRefPubMed
25.
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274:787CrossRefPubMed
26.
Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141PubMed
27.
28.
Jewett A, Wang MY, Teruel A, Poupak Z, Bostanian Z, Park NH (2003) Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor kappaB in HEp2 tumor cell line: effect on the function of natural killer cells. Hum Immunol 64:505CrossRefPubMed
29.
Greten FR, Karin M (2004) The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 206:193CrossRefPubMed
30.
Santos M, Perez P, Segrelles C, Ruiz S, Jorcano JL, Paramio JM (2003) Impaired NF-kappa B activation and increased production of tumor necrosis factor alpha in transgenic mice expressing keratin K10 in the basal layer of the epidermis. J Biol Chem 278:13422CrossRefPubMed
31.
Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A, Krampert M, Goebeler M, Gillitzer R, Israel A, Krieg T, Rajewsky K, Haase I (2002) TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417:861CrossRefPubMed
32.
Lukacher AE (2002) IFN-gamma suspends the killing license of anti-tumor CTLs. J Clin Invest 110:1407CrossRefPubMed
33.
DiDonato J, Mercurio F, Rosette C, Wu-Li J, Suyang H, Ghosh S, Karin M (1996) Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol 16:1295PubMed
34.
Jewett A, Cavalcanti M, Bonavida B, (1997) Pivotal role of endogenous TNF-alpha in the induction of functional inactivation and apoptosis in NK cells. J Immunol 159:4815PubMed
35.
36.
Seitz CS, Lin Q, Deng H, Khavari PA, (1998) Alterations in NF-kappaB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappaB. Proc Natl Acad Sci USA 95:2307CrossRefPubMed
37.
Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Tao S, Lin Q, Kubo Y, Khavari PA (2003) NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421:639CrossRefPubMed
38.
van Hogerlinden M, Rozell BL, Toftgard R, Sundberg JP, (2004) Characterization of the progressive skin disease and inflammatory cell infiltrate in mice with inhibited NF-kappaB signaling. J Invest Dermatol 123:101CrossRefPubMed
39.
40.
41.
van Hogerlinden M, Rozell BL, Ahrlund-Richter L, Toftgard R (1999) Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res 59:3299PubMed
42.
Thomas GR, Chen Z, Leukinova E, Van Waes C, Wen J (2004) Cytokines IL-1 alpha, IL-6, and GM-CSF constitutively secreted by oral squamous carcinoma induce down-regulation of CD80 costimulatory molecule expression: restoration by interferon gamma. Cancer Immunol Immunother 53:33CrossRefPubMed
43.
St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, Shi W, Qi F, Wu B, Sinha U, Jordan R, Wolinsky L, Park NH, Liu H, Abemayor E, Wong DT (2004) Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 130:929CrossRefPubMed
44.
45.
Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48CrossRefPubMed
46.
Morrison BE, Park SJ, Mooney JM, Mehrad B (2003) Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis. J Clin Invest 112:1862CrossRefPubMed
47.
Dorner BG, Scheffold A, Rolph MS, Huser MB, Kaufmann SH, Radbruch A, Flesch IE, Kroczek RA (2002) MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines. Proc Natl Acad Sci U S A 99:6181CrossRefPubMed
48.
Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, Speizer FE (1995) Aspirin and the risk of colorectal cancer in women. N Engl J Med 333:609CrossRefPubMed
49.
50.
Grilli M, Pizzi M, Memo M, Spano P (1996) Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 274:1383CrossRefPubMed
51.
Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77CrossRefPubMed
52.
Thun MJ, Namboodiri MM, Heath CW Jr (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325:1593PubMed
53.
Suh O, Mettlin C, Petrelli NJ (1993) Aspirin use, cancer, and polyps of the large bowel. Cancer 72:1171PubMedCrossRef
54.
Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Stolley PD, Shapiro S (1991) A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer. J Natl Cancer Inst 83:355PubMedCrossRef
Metadata
Title
Inhibition of nuclear factor kappa B (NFκB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation
Authors
Anahid Jewett
Nicholas A. Cacalano
Antonia Teruel
Marcela Romero
Marjan Rashedi
Meiying Wang
Hiromi Nakamura
Publication date
01-09-2006
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 9/2006
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-005-0093-7

Other articles of this Issue 9/2006

Cancer Immunology, Immunotherapy 9/2006 Go to the issue

Original Article

Effect of interleukin-18 on metastasis of mouse osteosarcoma cells

Original Article

NK cell activation by dendritic cell vaccine: a mechanism of action for clinical activity

Original Article

The in vitro antitumor effect and in vivo tumor-specificity distribution of human-mouse chimeric antibody against transferrin receptor

Original Article

A new way to generate cytolytic tumor-specific T cells: electroporation of RNA coding for a T cell receptor into T lymphocytes

Original Article

Growth inhibition of breast cancer cell lines overexpressing Her2/neu by a novel internalized fully human Fab antibody fragment

Original Article

T-cell receptor tetramer binding or the lack there of does not necessitate antigen reactivity in T-cell receptor transduced T cells
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
Image Credits