Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors

Abdeljabar El Andaloussi Section of Neurosurgery, The University of Chicago, Chicago, Illinois

Search for other papers by Abdeljabar El Andaloussi in
Current site
Google Scholar
PubMed
Close
 Ph.D.
,
Yu Han Section of Neurosurgery, The University of Chicago, Chicago, Illinois

Search for other papers by Yu Han in
Current site
Google Scholar
PubMed
Close
 B.S.
, and
Maciej S. Lesniak Section of Neurosurgery, The University of Chicago, Chicago, Illinois

Search for other papers by Maciej S. Lesniak in
Current site
Google Scholar
PubMed
Close
 M.D.
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $536.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $636.00
USD  $45.00
USD  $536.00
USD  $636.00
Print or Print + Online Sign in

Object

Regulatory CD4+CD25+ T cells have been shown to play an important role in the regulation of the immune response. Whereas the presence of these cells has been associated with immune suppression, the lack of regulatory T (Treg) cells has been shown to induce autoimmunity. The purpose of this study was to define the role of Treg cells in tumors of the central nervous system (CNS).

Methods

The authors implanted syngeneic GL261 tumor cells in the brains or flanks of C57BL/6 mice. The resulting tumors were later removed at specific time points, and the presence of tumor-infiltrating lymphocytes was analyzed by performing flow cytometry for the presence of Treg cells. In a separate experiment, mice with GL261 tumors were treated with injections of anti-CD25 monoclonal antibody (mAb) to determine whether depletion of Treg cells may have an impact on the length of survival in mice with brain tumors.

Tumor-infiltrating lymphocytes isolated from mice with GL261 tumors were found to have a significant increase in the presence of Treg cells compared with control lymphocytes (p < 0.05). Moreover, Treg cells isolated in murine brain tumors expressed FoxP3, CTLA-4, and CD62L. Mice treated with anti-CD25 mAb lived significantly longer than tumor-bearing control animals (p < 0.05). An analysis of brains in surviving animals showed a depletion of CD4+CD25+ T cells.

Conclusions

The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.

Abbreviations used in this paper:

CNS = central nervous system; CTL = cytotoxic T-lymphocyte; FACS = fluorescence-activated cell sorter; HO-1 = heme oxygenase-1; mAb = monoclonal antibody; PBS = phosphate-buffered saline; TIL = tumor-infiltrating lymphocyte; Treg = regulatory T.
  • Collapse
  • Expand
  • 1

    Abbas AK, , Lohr J, , Knoechel B, & Nagabhushanam V: T cell tolerance and autoimmunity. Autoimmun Rev 3:471475, 2004

  • 2

    Akasaki Y, , Black KL, & Yu JS: Dendritic cell-based immunotherapy for malignant gliomas. Expert Rev Neurother 5:497508, 2005

  • 3

    Akasaki Y, , Black KL, & Yu JS: T cell immunity in patients with malignant glioma: recent progress in dendritic cell-based immunotherapeutic approaches. Front Biosci 10:29082921, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Albers AE, , Ferris RL, , Kim GG, , Chikamatsu K, , DeLeo AB, & Whiteside TL: Immune responses to p53 in patients with cancer: enrichment in tetramer+ p53 peptide-specific T cells and regulatory T cells at tumor sites. Cancer Immunol Immunother 54:10721081, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Azuma T, , Takahashi T, , Kunisato A, , Kitamura T, & Hirai H: Human CD4+CD25+ regulatory T cells suppress NKT cell functions. Cancer Res 63:45164520, 2003

  • 6

    Baecher-Allan C, , Brown JA, , Freeman GJ, & Hafler DA: CD4+ CD25high regulatory cells in human peripheral blood. J Immunol 167:12451253, 2001

  • 7

    Baecher-Allan C, , Viglietta V, & Hafler DA: Human CD4+CD25+ regulatory T cells. Semin Immunol 16:8998, 2004

  • 8

    Balabanov R, , Beaumont T, & Dore-Duffy P: Role of central nervous system microvascular pericytes in activation of antigen-primed splenic T-lymphocytes. J Neurosci Res 55:578587, 1999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Bluestone JA, & Tang Q: How do CD4+CD25+ regulatory T cells control autoimmunity?. Curr Opin Immunol 17:638642, 2005

  • 10

    Cao D, , van Vollenhoven R, , Klareskog L, , Trollmo C, & Malmström V: CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther 6:R335R346, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Casares N, , Arribillaga L, , Sarobe P, , Dotor J, , Lopez-Diaz de Cerio A, & Melero I, et al.: CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-γ-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 171:59315939, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Choi BM, , Pae HO, , Jeong YR, , Kim YM, & Chung HT: Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression. Biochem Biophys Res Commun 327:10661071, 2005

  • 13

    Deininger MH, , Meyermann R, , Trautmann K, , Duffner F, , Grote EH, & Wickboldt J, et al.: Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression. Brain Res 882:18, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Delong P, , Carroll RG, , Henry AC, , Tanaka T, , Ahmad S, & Leibowitz MS, et al.: Regulatory T cells and cytokines in malignant pleural effusions secondary to mesothelioma and carcinoma. Cancer Biol Ther 4:342346, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Dunn GP, , Bruce AT, , Ikeda H, , Old LJ, & Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991998, 2002

  • 16

    Ehtesham M, , Kabos P, , Gutierrez MA, , Samoto K, , Black KL, & Yu JS: Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity against malignant glioma in rats. J Immunother 26:107116, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    El Andaloussi A, & Lesniak MS: An increase in CD4+CD25+ Foxp3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. Neurooncology 8:234243, 2006

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Fattorossi A, , Battaglia A, , Ferrandina G, , Buzzonetti A, , Legge F, & Salutari V, et al.: Lymphocyte composition of tumor draining lymph nodes from cervical and endometrial cancer patients. Gynecol Oncol 92:106115, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Fontenot JD, , Rasmussen JP, , Williams LM, , Dooley JL, , Farr AG, & Rudensky AY: Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329341, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Gavin M, & Rudensky A: Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr Opin Immunol 15:690696, 2003

  • 21

    Golgher D, , Jones E, , Powrie F, , Elliott T, & Gallimore A: Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 32:32673275, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Javia LR, & Rosenberg SA: CD4+CD25+ suppressor lymphocytes in the circulation of patients immunized against melanoma antigens. J Immunother 26:8593, 2003

  • 23

    Jones E, , Dahm-Vicker M, , Simon AK, , Green A, , Powrie F, & Cerundolo V, et al.: Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2:1, 2002

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Jonuleit H, , Schmitt E, , Stassen M, , Tuettenberg A, , Knop J, & Enk AH: Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:12851294, 2001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kohm AP, & Miller SD: Role of ICAM-1 and P-selectin expression in the development and effector function of CD4+CD25+ regulatory T cells. J Autoimmun 21:261271, 2003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Levings MK, , Sangregorio R, , Sartirana C, , Moschin AL, , Battaglia M, & Orban PC, et al.: Human CD25+CD4+ T suppressor cell clones produce transforming growth factor β, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med 196:13351346, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Liyanage UK, , Moore TT, , Joo HG, , Tanaka Y, , Herrmann V, & Doherty G, et al.: Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:27562761, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Maloy KJ, & Powrie F: Regulatory T cells in the control of immune pathology. Nat Immunol 2:816822, 2001

  • 29

    Marshall NA, , Christie LE, , Munro LR, , Culligan DJ, , Johnston PW, & Barker RN, et al.: Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:17551762, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Nagai H, , Horikawa T, , Hara I, , Fukunaga A, , Oniki S, & Oka M, et al.: In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer. Exp Dermatol 13:613620, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Nishie A, , Ono M, , Shono T, , Fukushi J, , Otsubo M, & Onoue H, et al.: Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5:11071113, 1999

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Onizuka S, , Tawara I, , Shimizu J, , Sakaguchi S, , Fujita T, & Nakayama E: Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res 59:31283133, 1999

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Piccirillo CA, & Shevach EM: Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 16:8188, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Rudensky A: FoxP3 and dominant tolerance. Philos Trans R Soc Lond B Biol Sci 360:16451646, 2005

  • 35

    Sakaguchi S, , Sakaguchi N, , Shimizu J, , Yamazaki S, , Sakihama T, & Itoh M, et al.: Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:1832, 2001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Schaefer C, , Kim GG, , Albers A, , Hoermann K, , Myers EN, & White-side TL: Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer 92:913920, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Shimizu J, , Suda T, , Yoshioka T, , Kosugi A, , Fujiwara H, & Hamaoka T: Induction of tumor-specific in vivo protective immunity by immunization with tumor antigen-pulsed antigen-presenting cells. J Immunol 142:10531059, 1989

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Shimizu J, , Yamazaki S, & Sakaguchi S: Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:52115218, 1999

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Sikorski CW, & Lesniak MS: Immunotherapy for malignant glioma: current approaches and future directions. Neurol Res 27:703716, 2005

  • 40

    Tambur AR, & Roitberg B: Immunology of the central nervous system. Neurol Res 27:675678, 2005

  • 41

    Tanaka H, , Tanaka J, , Kjaergaard J, & Shu S: Depletion of CD4+ CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes. J Immunother 25:207217, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    von Boehmer H: Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338344, 2005

  • 43

    Watanabe N, , Wang YH, , Lee HK, , Ito T, , Wang YH, & Cao W, et al.: Hassall’s corpuscles instruct dendritic cells to induce CD4+ CD25+ regulatory T cells in human thymus. Nature 436:11811185, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Wolf AM, , Wolf D, , Steurer M, , Gastl G, , Gunsilius E, & Grubeck-Loebenstein B: Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606612, 2003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Woo EY, , Chu CS, , Goletz TJ, , Schlienger K, , Yeh H, & Coukos G, et al.: Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61:47664772, 2001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Woo EY, , Yeh H, , Chu CS, , Schlienger K, , Carroll RG, & Riley JL, et al.: Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168:42724276, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Xia J, , Jiang X, , Huang Y, , Zhang K, , Xiao S, & Yang C: Anti-CD25 monoclonal antibody modulates cytokine expression and prolongs allografts survival in rats cardiac transplantation. Chin Med J (Engl) 116:432435, 2003

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Yu JS, , Liu G, , Ying H, , Yong WH, , Black KL, & Wheeler CJ: Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:49734979, 2004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Yu JS, , Wheeler CJ, , Zeltzer PM, , Ying H, , Finger DN, & Lee PK, et al.: Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res 61:842847, 2001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Yu P, , Lee Y, , Liu W, , Krausz T, , Chong A, & Schreiber H, et al.: Intratumoral depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201:779791, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 2347 533 33
Full Text Views 297 33 9
PDF Downloads 213 15 5
EPUB Downloads 0 0 0