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Open Access 01-06-2005 | Research article

Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

Authors: Alban Gervais, Jean Levêque, Françoise Bouet-Toussaint, Florence Burtin, Thierry Lesimple, Laurent Sulpice, Jean-Jacques Patard, Noelle Genetet, Véronique Catros-Quemener

Published in: Breast Cancer Research | Issue 3/2005

Abstract

Introduction

Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs.

Methods

The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells.

Results

Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR^-Lin^- cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR^-Lin^- cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid.

Conclusion

These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest.

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Schuler G, Schuler-Thurner B, Steinman RM: The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol. 2003, 15: 138-147. 10.1016/S0952-7915(03)00015-3.CrossRefPubMed

Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004, 10: 909-915. 10.1038/nm1100.CrossRefPubMedPubMedCentral

Lutz MB, Schuler G: Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?. Trends Immunol. 2002, 23: 445-449. 10.1016/S1471-4906(02)02281-0.CrossRefPubMed

Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N: Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med. 2000, 191: 423-433. 10.1084/jem.191.3.423.CrossRefPubMedPubMedCentral

Albert ML: Death-defying immunity: do apoptotic cells influence antigen processing and presentation. Nat Rev Immunol. 2004, 4: 223-231. 10.1038/nri11308.CrossRefPubMed

Bouet-Toussaint F, Patard J-J, Gervais A, Genetet N, de la Pintière CT, Rioux-Leclercq N, Toutirais O, Thirouard A-S, Ramée M-P, Catros-Quemener V: Cytotoxic effector cells with antitumor activity can be amplified ex vivo from biopsies or blood of patients with renal cell carcinoma for a cell therapy use. Cancer Immunol Immunother. 2003, 52: 699-707. 10.1007/s00262-003-0412-9.CrossRefPubMed

Kusmartsev S, Gabrilovich DI: Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother. 2002, 51: 293-298. 10.1007/s00262-002-0280-8.CrossRefPubMed

Almand B, Clark JI, Nikitina E, Beynen Jv, English NR, Knight SC, Carbone DP, Gabrilovich DI: Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001, 166: 678-689.CrossRefPubMed

Sallusto F, Lanzavecchia A: Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994, 179: 1109-1118. 10.1084/jem.179.4.1109.CrossRefPubMed

10.

Berger TG, Feuerstein B, Strasser E, Hirsch U, Schreiner D, Schuler G, Schuler-Thurner B: Large-scale generation of mature monocyte-derived dendritic cells for clinical application in cell factories. J Immunol Methods. 2002, 268: 131-140. 10.1016/S0022-1759(02)00189-8.CrossRefPubMed

11.

Lennon SV, Martin SJ, Cotter TG: Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli. Cell Prolif. 1991, 24: 203-214.CrossRefPubMed

12.

Spisek R, Chevallier P, Morineau N, Milpied N, Avet-Loiseau H, Harousseau J-L, Meflah K, Gregoire M: Induction of leukemia-specific cytotoxic response by cross-presentation of late-apoptotic leukemic blasts by autologous dendritic cells of nonleukemic origin. Cancer Res. 2002, 62: 2861-2868.PubMed

13.

Albert ML, Sauter B, Bhardwaj N: Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature. 1998, 392: 86-89. 10.1038/32183.CrossRefPubMed

14.

Cohen SS: A guide to the polyamines. A Guide to the Polyamines. 1998, New York: Oxford University Press, 595-

15.

Quemener V, Blanchard Y, Chamaillard L, Havouis R, Cipolla B, Moulinoux J-P: Polyamine deprivation : a new tool in cancer treatment. Anticancer Res. 1994, 14: 443-448.PubMed

16.

Seiler N, Atanassov CL: The natural polyamines and the immune system. Prog Drug Res. 1994, 43: 87-141.PubMed

17.

Quemener V, Bansard JY, Delamaire M, Roth S, Havouis R, Desury D, Moulinoux J-P: Red blood cell polyamines, anaemia and tumor growth in the rat. Eur J Cancer. 1996, 32A: 316-321. 10.1016/0959-8049(95)00584-6.CrossRefPubMed

18.

Chamaillard L, Catros-Quemener V, Delcros J-G, Bansard J-Y, Havouis R, Desury D, Commeurec A, Genetet N, Moulinoux J-P: Polyamine deprivation prevents the development of tumor-induced immune-suppression. Br J Cancer. 1997, 76: 365-370.CrossRefPubMedPubMedCentral

19.

Jonuleit H, Schmitt E, Steinbrink K, Enk AH: Dendritic cells as a tool to induce anergic and regulatory T cells. Trends immunol. 2001, 22: 394-400. 10.1016/S1471-4906(01)01952-4.CrossRefPubMed

20.

Chamaillard L, Quemener V, Havouis R, Moulinoux J-P: Polyamine deprivation stimulates Natural killer cell activity in cancerous mice. Anticancer Res. 1993, 13: 1027-1034.PubMed

21.

Bonnotte B, Favre N, Moutet M, Fromentin A, Solary E, Martin M, Martin F: Bcl2-mediated inhibition of apoptosis prevents immunogenicity and restores tumorigenicity of spontaneously regressive tumors. J Immunol. 1998, 161: 1433-1438.PubMed

22.

Menetrier-Caux C, Thomachot MC, Alberti L, Montmain G, Blay J-Y: IL-4 prevents the blockade of dendritic cell differenciation induced by tumor cells. Cancer Res. 2001, 61: 3096-3104.PubMed

23.

Satthaporn S, Robins A, Vassanasiri W, El-Sheemy M, Jibril JA, Clark D, Valerio D, Eremin O: Dendritic cells are dysfunctional in patients with operable breast cancer. Cancer Immunol Immunother. 2004, 53: 510-518. 10.1007/s00262-003-0485-5.CrossRefPubMed

24.

Zhang M, Caragine T, Wang H, Cohen P, Botchkina G, Soda K, Bianchi M, Ulrich P, Cerami A, Sherry B, Tracey K: Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J Exp Med. 1997, 185: 1759-1768. 10.1084/jem.185.10.1759.CrossRefPubMedPubMedCentral

25.

Ghiringhelli F, Larmonier L, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F: CD4⁺CD25⁺ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol. 2004, 34: 336-344. 10.1002/eji.200324181.CrossRefPubMed

26.

Chamaillard L, Catros-Quemener V, Moulinoux J-P: Synergistic activation of macrophage activity by polyamine deprivation and cyclophosphamide. Anticancer Res. 1997, 17: 1059-1066.PubMed

27.

Leveque J, Foucher F, Bansard J-Y, Havouis R, Grall J-Y, Moulinoux J-P: Polyamine profiles in tumor, normal tissue of the homologous breast, blood, and urine of breast cancer sufferers. Breast Cancer Res Treat. 2000, 60: 99-105. 10.1023/A:1006319818530.CrossRefPubMed

28.

Mohty M, Morbell S, Isnardon D, Sainty D, Arnoulet C, Gaugler B, Olive D: All-Trans retinoic acid skews monocyte differentiation into interleukin-12 secreting dendritic-like cells. Br J Haematol. 2003, 122: 829-836. 10.1046/j.1365-2141.2003.04489.x.CrossRefPubMed

29.

Avigan D, Vasir B, Gong J, Borges V, Wu Z, Uhl L, Atkins M, Mier J, McDermott D, Smith T, et al: Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses. Clin Cancer Res. 2004, 10: 4699-4708.CrossRefPubMed

Title: Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency
Authors: Alban Gervais
Jean Levêque
Françoise Bouet-Toussaint
Florence Burtin
Thierry Lesimple
Laurent Sulpice
Jean-Jacques Patard
Noelle Genetet
Véronique Catros-Quemener
Publication date: 01-06-2005
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 3/2005
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/bcr1001

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