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

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 6/2006

01-06-2006 | Original Article

Flow Cytometric analysis of Th1 and Th2 cytokines in PBMCs as a parameter of immunological dysfunction in patients of Superficial Transitional cell carcinoma of bladder

Authors: A. Agarwal, S. Verma, U. Burra, N. S. Murthy, N. K. Mohanty, S. Saxena

Published in: Cancer Immunology, Immunotherapy | Issue 6/2006

Login to get access

Abstract

Transitional cell carcinoma (TCC) is the commonest cancer of the bladder. Although majority of TCC can be diagnosed at an early stage and removed easily by transurethral resection of tumor (TURT), the management of this carcinoma is complicated due to frequent recurrences usually within 6 months to one-year period. An imbalance between the Th1 and Th2 immune responses has been attributed to immune dysregulation in various malignancies. The present study aims to evaluate the Th1 and Th2 balance in Peripheral Blood Mononuclear Cells of 41 TCC patients (20 recurrent and 21 non-recurrent) using flow cytometry. It also further assesses immunological and cellular factors influencing the anti-neoplastic activity of the TCC patients and in 21 normal healthy subjects in terms of their cytokine expression and various cell surface markers. The findings of the study revealed that the cell surface markers CD3+, CD4+ and CD8+ along with NK cells were found to be significantly lower in patients than healthy controls (p<0.01). The mean percent expression of CD4+ was significantly lower in patients showing recurrence (23.9±9.84) as compared to patients with non-recurrence (31.1±12.27). The percentage of CD4+T-cells (mean±SD) producing IFN-γ, IL-2 and TNF-α were statistically significantly reduced in patients (19.1±4.94, 52.3±20.86 and 12.8±4.49) as compared to healthy controls (23.3±3.67, 67.5±12.0 and 17.6±5.96 respectively), (p<0.01, 0.018, 0.001). On the contrary, the mean levels of IL-4, IL-6 and IL-10 in patients (63.8±17.01, 60.4±14.79 and 65.7±14.84 respectively) were significantly higher as compared to healthy controls (24.4±8.77, 26.5±5.28 and 20.6±3.81 respectively), (p<0.001). No statistically significant difference was observed in the cytokine expression between patients showing recurrence and non-recurrence. Patients with bladder cancer seem to develop a Th2 dominant status with a deficient type1 immune response. The lymphocyte evaluation along with cytokine measurement can provide a sensitive and valuable tool for evaluating the function of cell-mediated immunity in these patients and can also find application in therapeutic monitoring of bladder cancer patients as new targets for immunotherapy.
Literature
1.
Agarwal A, Rani M, Saha GK, Valarmathi TM, Bahadur S, Mohanti BK, Das SN (2003) Disregulated expression of the Th2 cytokine gene in patients with intraoral squamous cell carcinoma. Immunol Invest 32:17–30PubMedCrossRef
2.
Assenmacher M, Schmitz J, Radbruch A (1994) Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-gamma and in interleukin-4-expressing cells. Eur J Immunol 24:1097–101PubMedCrossRef
3.
Banat GA, Christ O, Cochlovius B, Pralle HB, Zoller M (2001) Tumour-induced suppression of immune response and its correction. Cancer Immunol Immunother 49:573–86PubMedCrossRef
4.
Boyum A (1968) Isolation of leucocytes from human blood. Further observations. Methylcellulose, dextran, and ficoll as erythrocyteaggregating agents. Scand J Clin Lab Invest 97:31–50
5.
Chen LK, Tourvieille B, Burns GF, Bach FH, Mathieu-Mahul D, Sasportes M, Bensussan A (1986) Interferon: a cytotoxic T lymphocyte differentiation signal. Eur J Immunol 16:767PubMedCrossRef
6.
Cher DJ, Mosmann TR (1987) Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol 138:3688–94PubMed
7.
Elson LH, Nutman TB, Metcalfe DD, Prussin C (1995) Flow cytometric analysis for cytokine production identifies T helper 1, T helper 2, and T helper 0 cells within the human CD4+CD27- lymphocyte subpopulation. J Immunol 154:4294–301PubMed
8.
Erard F, Wild MT, Garcia-Sanz JA, Le Gros G (1993) Switch of CD8 T cells to noncytolytic CD8-CD4-cells that make TH2 cytokines and help B cells. Science 260:1802–5PubMedCrossRef
9.
Gajewski TF, Fitch FW (1988) Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 140:4245–52PubMed
10.
Goto S, Sato M, Kaneko R, Itoh M, Sato S, Takeuchi S (1999) Analysis of Th1 and Th2 cytokine production by peripheral blood mononuclear cells as a parameter of immunological dysfunction in advanced cancer patients. Cancer Immunol Immunother 48:435–42PubMedCrossRef
11.
Halak BK, Maguire HC Jr, Lattime EC (1999) Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site. Cancer Res 59:911–7PubMed
12.
Hernandez-Pando R, Rook GA (1994) The role of TNF-alpha in T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance. Immunology 82:591–5PubMed
13.
Jackson AM, Ivshina AV, Senko O, Kuznetsova A, Sundan A, O’Donnell MA, Clinton S, Alexandroff AB, Selby PJ, James K, Kuznetsov VA (1998) Prognosis of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer by immunological urinary measurements:statistically weighted syndrome analysis. J Urol 159:1054–63PubMedCrossRef
14.
Jung T, Lack G, Schauer U, Uberuck W, Renz H, Gelfand EW, Rieger CH (1995) Decreased frequency of interferon-gamma- and interleukin-2-producing cells in patients with atopic diseases measured at the single cell level. J Allergy Clin Immunol 96:515–27PubMedCrossRef
15.
Jung T, Schauer U, Heusser C, Neumann C, Rieger C (1993) Detection of intracellular cytokines by flow cytometry. J Immunol Methods 159:197–207PubMedCrossRef
16.
Kaempfer R, Gerez L, Farbstein H, Madar L, Hirschman O, Nussinovich R, Shapiro A (1996) Prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 gene expression. J Clin Oncol 14:1778–86PubMed
17.
Kavanaugh DY, Carbone DP (1996) Immunologic dysfunction in cancer. Hematol Oncol Clin North Am 10:927–51PubMedCrossRef
18.
Klausner RD, Donaldson JG, Lippincott-Schwartz J (1992) Brefeldin A: insights into the control of membrane traffic and organelle structure. J Cell Biol 116:1071–80PubMedCrossRef
19.
Klein LT, Miller MI, Ikeguchi E, Buttyan R, Connor JP, Katz A, Raffo AJ and Olsson C (1996) Anti-fas antibody mediated apoptosis in bladder tumor cells: a potential intravesical therapeutic agent. Proc Annu Meet Amer Assoc cancer Res 37:A103
20.
Kurisu H, Matsuyama H, Ohmoto Y, Shimabukuro T, Naito K (1994) Cytokine-mediated antitumor effect of bacillus Calmette-Guerin on tumor cells in vitro. Cancer Immunol Immunother 39:249–53PubMedCrossRef
21.
Lattime EC, Gomella LG, McCue PA (1992) Murine bladder carcinoma cells present antigen to BCG-specific CD4+ T-cells. Cancer Res 52:4286–90PubMed
22.
Lee KY, Goedegebuure PS, Linehan DC, Eberlein TJ (1995) Immunoregulatory effects of CD4+ T helper subsets in human melanoma. Surgery 117:365–72PubMedCrossRef
23.
24.
Lord EM, Frelinger JG (1998) Tumor immunotherapy: cytokines and antigen presentation. Cancer Immunol Immunother 46:75–81PubMedCrossRef
25.
Luo Y, Szilvasi A, Chen X, DeWolf WC, O’Donnell MA (1996) A novel method for monitoring Mycobacterium bovis BCG trafficking with recombinant BCG expressing green fluorescent protein. Clin Diagn Lab Immunol 3:761–8PubMed
26.
Maeda H, Kuwahara H, Ichimura Y, Ohtsuki M, Kurakata S, Shiraishi A (1995) TGF-beta enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. J Immunol 155:4926–32PubMed
27.
Manson LA (1991) Does antibody-dependent epitope masking permit progressive tumor growth in the face of cell-mediated cytotoxicity? Immunol Today 12:352–5PubMedCrossRef
28.
Meyaard L, Hovenkamp E, Keet IP, Hooibrink B, de Jong IH, Otto SA, Miedema F (1996) Single cell analysis of IL-4 and IFN-gamma production by T cells from HIV-infected individuals: decreased IFN-gamma in the presence of preserved IL-4 production. J Immunol 157:2712–18PubMed
29.
Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–73PubMedCrossRef
30.
O’Donnell MA, Luo Y, Chen X, Szilvasi A, Hunter SE, Clinton SK (1999) Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guerin. J Immunol 163:4246–52PubMed
31.
32.
Olsson CA, Rao CN, Menzoian JO, Byrd WE (1972) Immunologic unreactivity in bladder cancerpatients. J Urol107:607–9PubMed
33.
Openshaw P, Murphy EE, Hosken NA, Maino V, Davis K, Murphy K, O’Garra (1995) A Heterogeneity of intracellular cytokine synthesis at the single-cell level in polarized T helper 1 and T helper 2 populations. J Exp Med 182:1357–67PubMedCrossRef
34.
Paul WE, Seder RA (1994) Lymphocyte responses and cytokines. Cell 2876:241–51CrossRef
35.
Pellegrini P, Berghella AM, Del Beato T, Cicia S, Adorno D, Casciani CU (1996) Disregulation in TH1 and TH2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression. Cancer Immunol Immunother 42:1–8PubMedCrossRef
36.
Picker LJ, Singh MK, Zdraveski Z, Treer JR, Waldrop SL, Bergstresser PR, Maino VC (1995) Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood 86:1408–19PubMed
37.
Powrie F, Menon S, Coffman RL (1993) Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol 23:3043–9PubMedCrossRef
38.
Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF (1992) Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 147:1636–42PubMed
39.
Pryor K, Stricker P, Russell P, Golovsky D, Penny R (1995) Antiproliferative effects of bacillus Calmette-Guerin and interferon alpha 2b on human bladder cancer cells in vitro. Cancer Immunol Immunother 41:309–16PubMedCrossRef
40.
Pyrah LN, Raper FP, Thomas, GM (1964) Report of a follow-up of papillary tumours of the bladder. Br J Urol 36:14–25PubMedCrossRef
41.
Scott, P (1991) IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol 147:3149–55PubMed
42.
Seder RA, Paul WE (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 12:635–73PubMedCrossRef
43.
Silverberg E, Lubere JA (1988) Cancer statstics 1988. CA Cancer J clin 38:5–22PubMed
44.
Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, Vitetta ES (1988) Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 334:255–8PubMedCrossRef
45.
Swain SL, Weinberg AD, English M, Huston G (1990) IL-4 directs the development of Th2-like helper effectors. J Immunol 145:3796–806PubMed
46.
Torti FM, Lum BL (1986) Superficial carcinoma of bladder: natural history and the role of interferons. Semin oncol 13:57–60PubMed
47.
Tripp CS, Wolf SF, Unanue ER (1993) Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A 90:3725–9PubMedCrossRef
48.
Zaks TZ, Chappell DB, Rosenberg SA, Restifo NP (1999) Fas-mediated suicide of tumor-reactive T cells following activation by specific tumor: selective rescue by caspase inhibition. J Immunol 162:3273–9PubMed
49.
Zielinski CC, Mueller C, Tyl E, Tichatschek E, Kubista E, Spona J (1990) Impaired production of tumor necrosis factor in breast cancer. Cancer 66:1944–8PubMedCrossRef
50.
Zlotta AR, Drowart A, Huygen K, De Bruyn J, Shekarsarai H, Decock M, Pirson M, Jurion F, Palfliet K, Denis O, Mascart F, Simon J, Schulman CC, Van Vooren JP (1997) Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette-Guerin (BCG) in patients with superficial bladder cancer. Clin Exp Immunol 109:157–65PubMedCrossRef
Metadata
Title
Flow Cytometric analysis of Th1 and Th2 cytokines in PBMCs as a parameter of immunological dysfunction in patients of Superficial Transitional cell carcinoma of bladder
Authors
A. Agarwal
S. Verma
U. Burra
N. S. Murthy
N. K. Mohanty
S. Saxena
Publication date
01-06-2006
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 6/2006
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-005-0045-2

Other articles of this Issue 6/2006

Cancer Immunology, Immunotherapy 6/2006 Go to the issue

Original Article

Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells

Original Article

Broad antitumor protection by dendritic cells administered to CD8α knock out mice

Original Article

Vaccination with mRNAs encoding tumor-associated antigens and granulocyte-macrophage colony-stimulating factor efficiently primes CTL responses, but is insufficient to overcome tolerance to a model tumor/self antigen

Short Communication

Expression of CD45 and proliferative response to CD3 as suitable classification markers of patients with gastric adenocarcinoma

Perspectives

ESTDAB: a collection of immunologically characterised melanoma cell lines and searchable databank

Original Article

Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab
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