Skip to main content
Top
Published in: Cancer Immunology, Immunotherapy 10/2013

01-10-2013 | Original Article

Dendritic cell phenotype can be improved by certain chemotherapies and is associated with alterations to p21waf1/cip1

Authors: Wai Man Liu, Katherine Ann Scott, Mareike Thompson, Angus George Dalgleish

Published in: Cancer Immunology, Immunotherapy | Issue 10/2013

Login to get access

Abstract

Introduction

Dendritic cells (DCs) possess the capacity to elicit immune responses against harmful antigens and have been used in DC-vaccines to stimulate the immune system to engage cancer cells. However, a lack of an appreciation of the quality of the DC that is used and/or the monocyte from which it is derived has limited their successful incorporation into treatment strategies.

Methods

In the current study, we explored the relationship between cytokine receptor expression on the monocytes and its subsequent development into DCs. The significance of p21 expression in DCs during differentiation was also studied, as was the effect that manipulating this with chemotherapy may have on DC quality.

Results

DCs separated into two groups based on their ability to respond to a maturation stimulus. This quality correlated with a particular receptor profile of granulocyte–macrophage colony-stimulating factor and interleukin 4 expressed on the monocytes from which they were derived. DC quality was also associated with p21 expression, and artificially increasing their levels in DCs by using some chemotherapy improved function.

Conclusions

Overall, these studies have highlighted a role for common chemotherapy in activating p21 in DCs, which is a prerequisite for good DC function.
Literature
1.
go back to reference Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378):480–489PubMedCrossRef Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480(7378):480–489PubMedCrossRef
2.
go back to reference Palucka K, Ueno H, Banchereau J (2011) Recent developments in cancer vaccines. J Immunol 186(3):1325–1331PubMedCrossRef Palucka K, Ueno H, Banchereau J (2011) Recent developments in cancer vaccines. J Immunol 186(3):1325–1331PubMedCrossRef
3.
go back to reference Dalgleish AG (2011) Therapeutic cancer vaccines: why so few randomised phase III studies reflect the initial optimism of phase II studies. Vaccine 29(47):8501–8505PubMedCrossRef Dalgleish AG (2011) Therapeutic cancer vaccines: why so few randomised phase III studies reflect the initial optimism of phase II studies. Vaccine 29(47):8501–8505PubMedCrossRef
4.
go back to reference Liu WM, Dalgleish AG (2012) The potential beneficial effects of drugs on the immune response to vaccination. Semin Oncol 39(3):340–347PubMedCrossRef Liu WM, Dalgleish AG (2012) The potential beneficial effects of drugs on the immune response to vaccination. Semin Oncol 39(3):340–347PubMedCrossRef
5.
go back to reference Liu WM, Dennis JL, Fowler DW, Dalgleish AG (2012) The gene expression profile of unstimulated dendritic cells can be used as a predictor of function. Int J Cancer 130(4):979–990PubMedCrossRef Liu WM, Dennis JL, Fowler DW, Dalgleish AG (2012) The gene expression profile of unstimulated dendritic cells can be used as a predictor of function. Int J Cancer 130(4):979–990PubMedCrossRef
6.
go back to reference Lanza F, Castagnari B, Rigolin G, Moretti S, Latorraca A, Ferrari L, Bardi A, Castoldi G (1997) Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells. Leukemia 11(10):1700–1710PubMedCrossRef Lanza F, Castagnari B, Rigolin G, Moretti S, Latorraca A, Ferrari L, Bardi A, Castoldi G (1997) Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells. Leukemia 11(10):1700–1710PubMedCrossRef
7.
go back to reference Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17:701–738PubMedCrossRef Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 17:701–738PubMedCrossRef
8.
go back to reference Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512PubMedCrossRef Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512PubMedCrossRef
10.
go back to reference Coqueret O (2003) New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13(2):65–70PubMedCrossRef Coqueret O (2003) New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13(2):65–70PubMedCrossRef
11.
go back to reference Santiago-Raber ML, Lawson BR, Dummer W, Barnhouse M, Koundouris S, Wilson CB, Kono DH, Theofilopoulos AN (2001) Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J Immunol 167(7):4067–4074PubMed Santiago-Raber ML, Lawson BR, Dummer W, Barnhouse M, Koundouris S, Wilson CB, Kono DH, Theofilopoulos AN (2001) Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J Immunol 167(7):4067–4074PubMed
12.
go back to reference Jackson SK, DeLoose A, Gilbert KM (2001) Induction of anergy in Th1 cells associated with increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. J Immunol 166(2):952–958PubMed Jackson SK, DeLoose A, Gilbert KM (2001) Induction of anergy in Th1 cells associated with increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. J Immunol 166(2):952–958PubMed
13.
go back to reference Gazitt Y, Reddy SV, Alcantara O, Yang J, Boldt DH (2001) A new molecular role for iron in regulation of cell cycling and differentiation of HL-60 human leukemia cells: iron is required for transcription of p21(WAF1/CIP1) in cells induced by phorbol myristate acetate. J Cell Physiol 187(1):124–135PubMedCrossRef Gazitt Y, Reddy SV, Alcantara O, Yang J, Boldt DH (2001) A new molecular role for iron in regulation of cell cycling and differentiation of HL-60 human leukemia cells: iron is required for transcription of p21(WAF1/CIP1) in cells induced by phorbol myristate acetate. J Cell Physiol 187(1):124–135PubMedCrossRef
14.
go back to reference Kramer JL, Baltathakis I, Alcantara OS, Boldt DH (2002) Differentiation of functional dendritic cells and macrophages from human peripheral blood monocyte precursors is dependent on expression of p21 (WAF1/CIP1) and requires iron. Br J Haematol 117(3):727–734PubMedCrossRef Kramer JL, Baltathakis I, Alcantara OS, Boldt DH (2002) Differentiation of functional dendritic cells and macrophages from human peripheral blood monocyte precursors is dependent on expression of p21 (WAF1/CIP1) and requires iron. Br J Haematol 117(3):727–734PubMedCrossRef
15.
go back to reference Jonuleit H, Kühn U, Müller G, Steinbrink K, Paragnik L, Schmitt E, Knop J, Enk AH (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27(12):3135–3142PubMedCrossRef Jonuleit H, Kühn U, Müller G, Steinbrink K, Paragnik L, Schmitt E, Knop J, Enk AH (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27(12):3135–3142PubMedCrossRef
16.
go back to reference Liu WM, Fowler DW, Smith P, Dalgleish AG (2010) Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer 102(1):115–123PubMedCrossRef Liu WM, Fowler DW, Smith P, Dalgleish AG (2010) Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer 102(1):115–123PubMedCrossRef
17.
go back to reference Tuana G, Volpato V, Ricciardi-Castagnoli P, Zolezzi F, Stella F, Foti M (2011) Classification of dendritic cell phenotypes from gene expression data. BMC Immunol 12:50–62PubMedCrossRef Tuana G, Volpato V, Ricciardi-Castagnoli P, Zolezzi F, Stella F, Foti M (2011) Classification of dendritic cell phenotypes from gene expression data. BMC Immunol 12:50–62PubMedCrossRef
18.
go back to reference Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7(1):19–30PubMedCrossRef Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7(1):19–30PubMedCrossRef
19.
go back to reference Guthridge MA, Powell JA, Barry EF, Stomski FC, McClure BJ, Ramshaw H, Felquer FA, Dottore M, Thomas DT, To B, Begley CG, Lopez AF (2006) Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch. EMBO J 25(3):479–489PubMedCrossRef Guthridge MA, Powell JA, Barry EF, Stomski FC, McClure BJ, Ramshaw H, Felquer FA, Dottore M, Thomas DT, To B, Begley CG, Lopez AF (2006) Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch. EMBO J 25(3):479–489PubMedCrossRef
20.
go back to reference Sallusto F, Lanzavecchia A (1994) 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 179(4):1109–1118PubMedCrossRef Sallusto F, Lanzavecchia A (1994) 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 179(4):1109–1118PubMedCrossRef
21.
go back to reference Roy KC, Bandyopadhyay G, Rakshit S, Ray M, Bandyopadhyay S (2004) IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1a(dim), CD83(+) myeloid dendritic cell subset. J Cell Sci 117(16):3435–3445PubMedCrossRef Roy KC, Bandyopadhyay G, Rakshit S, Ray M, Bandyopadhyay S (2004) IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1a(dim), CD83(+) myeloid dendritic cell subset. J Cell Sci 117(16):3435–3445PubMedCrossRef
22.
go back to reference Conti L, Cardone M, Varano B, Puddu P, Belardelli F, Gessani S (2008) Role of the cytokine environment and cytokine receptor expression on the generation of functionally distinct dendritic cells from human monocytes. Eur J Immunol 38(3):750–762PubMedCrossRef Conti L, Cardone M, Varano B, Puddu P, Belardelli F, Gessani S (2008) Role of the cytokine environment and cytokine receptor expression on the generation of functionally distinct dendritic cells from human monocytes. Eur J Immunol 38(3):750–762PubMedCrossRef
23.
go back to reference Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M, Mahmoudi A, Cathers B, Rychak E, Gaidarova S, Chen R, Schafer PH, Handa H, Daniel TO, Evans JF, Chopra R (2012) Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26(11):2326–2335PubMedCrossRef Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M, Mahmoudi A, Cathers B, Rychak E, Gaidarova S, Chen R, Schafer PH, Handa H, Daniel TO, Evans JF, Chopra R (2012) Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26(11):2326–2335PubMedCrossRef
24.
go back to reference Motoshima H, Goldstein BJ, Igata M, Araki E (2006) AMPK and cell proliferation–AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol 574(1):63–71PubMedCrossRef Motoshima H, Goldstein BJ, Igata M, Araki E (2006) AMPK and cell proliferation–AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol 574(1):63–71PubMedCrossRef
25.
go back to reference Lee KM, Jo S, Kim H, Lee J (1813) Park CS (2011) Functional modulation of AMP-activated protein kinase by cereblon. Biochim Biophys Acta 3:448–455 Lee KM, Jo S, Kim H, Lee J (1813) Park CS (2011) Functional modulation of AMP-activated protein kinase by cereblon. Biochim Biophys Acta 3:448–455
26.
go back to reference Henry JY, Labarthe MC, Meyer B, Dasgupta P, Dalgleish AG, Galustian C (2013) Enhanced cross-priming of naive CD8+ T cells by DCs treated by the IMiDs® immunomodulatory compounds Lenalidomide and Pomalidomide. Immunology. doi:10.1111/imm.12087 Henry JY, Labarthe MC, Meyer B, Dasgupta P, Dalgleish AG, Galustian C (2013) Enhanced cross-priming of naive CD8+ T cells by DCs treated by the IMiDs® immunomodulatory compounds Lenalidomide and Pomalidomide. Immunology. doi:10.​1111/​imm.​12087
27.
go back to reference Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105(7):2862–2868PubMedCrossRef Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105(7):2862–2868PubMedCrossRef
28.
go back to reference Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11(18):6713–6721PubMedCrossRef Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11(18):6713–6721PubMedCrossRef
Metadata
Title
Dendritic cell phenotype can be improved by certain chemotherapies and is associated with alterations to p21waf1/cip1
Authors
Wai Man Liu
Katherine Ann Scott
Mareike Thompson
Angus George Dalgleish
Publication date
01-10-2013
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 10/2013
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-013-1456-0

Other articles of this Issue 10/2013

Cancer Immunology, Immunotherapy 10/2013 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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