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Research Article

The Contribution of Vascular Endothelial Growth Factor to the Induction of Regulatory T-Cells in Malignant Effusions

JUNJI WADA, HIROYUKI SUZUKI, RYOUTA FUCHINO, AKIO YAMASAKI, SHUNTARO NAGAI, KOUSUKE YANAI, KENICHIRO KOGA, MASAFUMI NAKAMURA, MASAO TANAKA, TAKASHI MORISAKI and MITSUO KATANO
Anticancer Research March 2009, 29 (3) 881-888;
JUNJI WADA
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HIROYUKI SUZUKI
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RYOUTA FUCHINO
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AKIO YAMASAKI
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SHUNTARO NAGAI
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KOUSUKE YANAI
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KENICHIRO KOGA
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MASAFUMI NAKAMURA
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MASAO TANAKA
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TAKASHI MORISAKI
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MITSUO KATANO
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  • For correspondence: mkatano@tumor.med.kyushu-u.ac.jp
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Abstract

It has been suggested that immunosuppressive cytokines such as transforming growth factor β (TGF-β) and interleukin 10 play an important role in the induction and/or maintenance of regulatory T-cells (Tregs) in patients with cancer. In the present study, whether or not vascular endothelial growth factor (VEGF) contributes to the induction and/or maintenance of Tregs was examined, because of experience with a patient in whom a positive correlation between VEGF concentration and the percentage of Tregs (% Tregs) among the total CD4+ T-cells in the pleural effusion was found during dendritic cell activated lymphocyte therapy. CD4+CD25high T-cells were estimated as Tregs in the present study. In an in vitro experimental system, VEGF-containing malignant effusions increased the % Tregs in autologous peripheral blood mononuclear cells (PBMCs), which could be suppressed by the addition of a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]). When VEGF-producing hepatic carcinoma cells were mix-cultured with PBMCs, the % Tregs increased and this increase was also suppressed by the addition of bevacizumab. Whether or not bevacizumab can affect the % Tregs of PBMCs in patients with colon cancer was also examined. Three out of four patients showed a significant decrease of the % Tregs after intravenous injection of bevacizumab. Interestingly, the expression of VEGF receptor-2 (VEGFR-2) was higher in Tregs than in other CD4+ T-cells. Taken together, the data presented here indicate a contribution of VEGF to induction and/or maintenance of Tregs in patients with cancer.

  • Regulatory T-cells
  • human FOXP3
  • VEGF
  • IL-10
  • TGF-β
  • immunotherapy
  • tumor immunity
  • survival

Abbreviations: IL-10, Interleukin-10; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; Tregs, regulatory T-cells; Foxp3, forkhead box protein 3; FACS, fluorescence-activated cell sorting; DC, dendritic cells; DAK, dendritic cell-activated lymphocytes; PBMCs, peripheral blood mononuclear cells.

It has been reported that several immunosuppressive cytokines, including transforming growth factor-β (TGF-β), IL-10 (interleukin-10) and vascular endothelial growth factor (VEGF) are detected in the tumor microenviroment (1-7) and that they act as an obstacle against antitumor immunity (8-10). Various types of tumor can secrete a large quantity of VEGF and this ability is often associated with a poor prognosis (11-14). VEGF is known to play a crucial role in tumor angiogenesis. On the other hand, VEGF is also known to play an important role in promoting and sustaining the nonresponsiveness of the immune system to growing tumors (15-18). Thus VEGF may act not only as a promoting factor in tumor growth, but also as a suppressing factor in anti-tumor immunity. Therefore, a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biological activity of human VEGF has been approved for the first-line treatment of patients with metastatic colorectal cancer (19).

Recently, a unique CD4+ T-cell population, which is designated regulatory T-cells (Tregs) has been identified. Tregs have been shown to contribute to the prevention of autoimmune disorders by controlling the activity of autoreactive T-cells (20-22). Tregs are increased in the peripheral blood and cancer tissues in several types of advanced cancer (23-28) and these increases in Tregs may play critical roles in immune tolerance of carcinomas (29), since most tumor-associated antigens are self-antigens. Thus, several clinicians are now evaluating the depletion of Tregs in an attempt to improve the therapeutic effect of tumor immunotherapies such as monocyte-derived dendritic cell (DC)-based vaccine therapy and activated lymphocyte infusion therapy. In fact, several reports have shown that depletion of Tregs results in increased immune responses towards tumors in animal tumor models (30-36). Interestingly, the contribution of immunosuppressive cytokines such as TGF-β and IL-10 to the induction or maintenance of Tregs has been reported previously (9, 37).

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Table I.

Profiles of cancer patients.

In the present study, whether or not VEGF could participate in the induction or maintenance of Tregs in patients with cancer was examined.

Materials and Methods

Cells. VEGF-producing human hepatocellular carcinoma cells, HepG2, were maintained at 37°C under a humidified atmosphere of 5% CO2 and 95% air in RPMI-1640 medium (Nacalai tesque, Kyoto, Japan) supplemented with 10% fetal bovine serum (FBS; Life Technologies, Grand Island, NY, USA) and antibiotics (100 units/ml penicillin and 100 μg/ml streptomycin; Meijiseika, Tokyo, Japan) (38).

Patients and therapeutic protocols. Eighteen patients with malignant effusions and multiple metastases were studied according to a protocol which was approved by the Kyushu University Ethics Committee, Japan. The patient profiles are shown in Table I. Seventeen out of the 18 patients received immunotherapy consisting of an intravenous injection of 1-10×108 tumor-pulsed DC-activated lymphocytes (DAK), in addition some patients also received a subcutaneous injection of 2-30×106 mature DCs loaded with necrotic autologous tumor cells (DC vaccine) into the left supra-clavicular area every 2 or 4 weeks (39). In principle, this immunotherapy was continued for as long as possible in the outpatient clinic.

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Table II.

Profiles of patients who received bevacizumab.

Preparation of DAK and DC vaccine. Autologous tumor-pulsed DCs (DC vaccine) were prepared as described previously (39). Briefly, immature DCs were prepared from peripheral blood mononuclear cells (PBMCs) using recombinant human granulocyte/monocyte colony-stimulating factor (GM-CSF; 200 ng/ml; Novartis Pharma, Basel, Switzerland) and recombinant human IL-4 (500 U/ml; Ono, Tokyo, Japan) for 7 days. Tumor cells obtained from tumor masses or malignant effusions were lysed by five freeze-thaw cycles (necrotic tumor cells). The immature DCs were incubated with the necrotic tumor cells overnight and then cultured for 2 days with tumor-pulsed DCs in medium containing tumor necrosis factor-α (TNF-α; 1000 U/ml; R and D Systems Inc., Minneapolis, MN, USA) and prostaglandin E2 (PGE2; 1 μg/ml; Sigma, St. Louis, MO, USA).

For preparation of the DAKs, non-adherent cells from each patient's PBMCs were cultured with tumor-pulsed DCs for 1 week in Hy-medium containing 175 JRU/ml of human recombinant IL-2 (Nipro, Tokyo, Japan).

Bevacizumab (Avastin)-based therapy. Four patients with advanced colon cancer with multiple metastases received bevacizumab (5 mg/kg) every 2 weeks by intravenous injection (Table II).

Figure 1.
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Figure 1.

Kinetic study of % Tregs and VEGF concentration in malignant effusion collected from a patient with ovarian cancer during DAK therapy.

Figure 2.
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Figure 2.

The relationship between % Tregs and VEGF concentration in malignant effusions. % Tregs of EDMCs and VEGF concentration in malignant effusions collected from the 18 cancer patients, as listed in Table I.

Flow cytometric analysis. The malignant effusion-derived mononuclear cells (EDMCs) and the PBMCs were stained with anti-CD25, anti-CD4, anti-CD8 (BD Biosciences, Tokyo, Japan) or anti-human VEGF receptor-2 (VEGFR-2; R and D Systems). Intracellular staining of forkhead box protein 3 (FOXP3) was conducted using a PE-conjugated anti-human FOXP3 Staining Set (clone PCH101; e-Bioscience, San Diego, CA, USA) according to the manufacturer's instructions. Two- or three-color flow cytometry was performed using fluorescence-activated cell sorting (FACS) Calibur™ (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA). CD25high cells or FOXP3+ cells after gating of CD4+ lymphocytes were evaluated as Tregs (25, 28, 40). The percentage of Tregs among the total CD4+ T-cells was represented as % Tregs.

Figure 3.
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Figure 3.

The induction of Tregs in PBMCs by malignant effusion and its suppression by bevacizumab. PBMCs collected from a patient with cholangio-carcinoma were cultured for 7 days with autologous patient-derived ascitic fluid (VEGF: 3353 pg/ml). Bev: bevacizumab.

Transwell experiments. PBMCs (1×106 cells) from a healthy volunteer and HepG2 cells (5×105 cells) were cultured separately using polycarbonate 24-well transwell inserts (TR; 0.4 μM) (Becton Dickinson Labware, NJ, USA). The cells were suspended in RPMI-1640 containing 1% albumin and 2% human serum with or without bevacizumab (10 μg/ml) and cultured for 7 days.

ELISA. The culture supernatants or malignant effusions were collected and the concentrations of VEGF were measured by an ELISA kit (Biosource International, Inc, Camarillo, CA, USA).

Statistical analysis. Fisher's exact probability test was used for the statistical analyses. The data were analyzed with a SAS statistical software package (Abacus Concepts, Berkeley, CA, USA). Values of p<0.05 were considered to indicate statistical significance.

Figure 4.
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Figure 4.

Decrease of % Tregs in colon cancer patients by bevacizumab. % Tregs in PBMCs before (solid column) and after (open column) the intravenous injection of bevacizumab in four patients with colon cancer, as shown in Table II.

Results

Case report. A 70-year-old female presented with stage IV ovarian cancer with malignant pleural effusion. She had received prior second-line chemotherapy and was evaluated as having progressive disease at the time of entry into the immunotherapy. Before therapy, the % Tregs of the EDMCs and VEGF concentration in pleural effusion were 9.14% and 1,186.0 pg/ml, respectively. During DAK therapy, the change in % Tregs roughly paralleled the change in VEGF concentration (Figure 1).

Relationship between % Tregs and VEGF concentration in malignant effusions. Since an association between Tregs and VEGF was suggested, the % Tregs of EDMCs and VEGF concentration was measured in the malignant effusions collected from the 18 patients (Table I). Unfortunately, there was no significant correlation between the % Tregs and the VEGF concentration (Figure 2).

Induction of Tregs in PBMCs by malignant effusion and its suppression by bevacizumab. When PBMCs collected from a patient with cholangio-carcinoma were cultured for 7 days with the patient-derived ascetic fluid (VEGF: 3,353 pg/ml), the % Tregs in the PBMCs increased, and its increase was significantly suppressed by the addition of bevacizumab at the initiation of culture (Figure 3).

Figure 5.
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Figure 5.

The induction of Tregs in PBMCs by HepG2 cells, and its suppression by bevacizumab. PBMCs from a healthy volunteer and HepG2 cells which secrete a large a quantity of VEGF (VEGF: 2,036 pg/ml). PBMCs were cultured separately using a transwell culture system.

Figure 6.
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Figure 6.

The expression of VEGFR-2 on Tregs. VEGFR-2 expression was examined in gated-lymphocyte populations using three-color flow cytometry analysis in PBMCs collected from two healthy volunteers (Case 1 and Case 2). MFI: mean fluorescent intensity.

Decrease of % Tregs in patients with colon cancer by bevacizumab. The % Tregs in the PBMCs was measured before and after the intravenous injection of bevacizumab in four patients with colon cancer (Table II). In three out of the four patients, bevacizumab therapy significantly reduced the % Tregs (Figure 4). No particular adverse reactions occurred during the observation period.

Induction of Tregs in PBMCs by HepG2 cells and its suppression by bevacizumab. To confirm a possibility that VEGF can induce Tregs in PBMCs, PBMCs were cultured separately using a transwell culture system with HepG2 cells, which secrete a large quantity of VEGF. The HepG2 cells increased significantly the % Tregs and bevacizumab significantly reduced the % Tregs to almost the control level (Figure 5).

Expression of VEGFR-2 on Tregs. The expression of VEGF receptor-2 (VEGFR-2) was significantly higher on the Tregs compared with other CD4+ T-cells in a healthy volunteer (Case 1, Figure 6, left panel). On the other hand, both CD4+CD25low T-cells and Tregs expressed VEGFR-2 in a second healthy volunteer (Case 2, Figure 6, right panel), but the grade of its expression was significantly lower compared with Case 1.

Discussion

In the present study, it was found that VEGF may play an important role in the induction or maintenance of Tregs in a tumor microenvironment. In addition, for the first time it was shown that VEGFR2 is expressed on Tregs in some cases.

As several investigators have indicated (23, 24), the % Tregs was significantly increased in malignant effusions compared with that in PBMCs from healthy volunteers (data not shown). Immunosuppressive cytokines such as TFG-β and IL-10, which contribute to the induction and/or maintenance of Tregs, are also known to increase in malignant effusions. Although these cytokines were detected in most of the malignant effusions examined, there was no significant correlation between the % Tregs and the concentration of these cytokines (data not shown). A patient showing increased % Tregs in EDMCs and VEGF in the malignant effusion was encountered. Interestingly, during DAK therapy, the change in % Tregs paralleled changes in VEGF concentration (Figure 1). We hypothesized that there is some link between Tregs and VEGF which may be supported by the following data. First, when a patient's PBMCs were used as target cells, a malignant effusion containing a large quantity of VEGF increased the % Tregs in the PBMCs, which was inhibited by bevacizumab (Figure 3). Second, VEGF-producing HepG2 cells increased the % Tregs in PBMCs and this increase was also inhibited by the presence of bevacizumab (Figure 5). In addition, the administration of bevacizumab to treat patients with advanced colon cancer significantly reduced the % Tregs in the PBMCs in three out of the four patients (Figure 4). These in vivo data may also indirectly support our hypothesis. Interestingly, Li et al. (41) reported that the overexpression of VEGF from tumors resulted in increased numbers of Tregs in the tumor. Although these findings strongly suggest a link between the induction of Tregs and VEGF, there was no significant correlation of the % Tregs in the EDMCs and VEGF concentration in the malignant effusions (Figure 2). In order to address these contradictory results, the expression status of VEGFR on the Tregs was examined. VEGF activity is mediated essentially through two receptors, VEGFR-1 and VEGFR-2 (42, 43) and VEGFR-2 seems to be responsible for the angiogenic effect of VEGF. As expected, VEGFR-2 was expressed on the Tregs of the PBMCs collected from two healthy volunteers (Figure 6). However, the level of expression of VEGFR-2 differed between the two people. These preliminary data suggest that differing levels of VEGFR-2 expression on Tregs in individuals may result in different reactions of the Tregs to VEGF. However, no definite answer was found for the lack of correlation between the % Tregs in the EDMCs and the VEGF concentration in the malignant effusions. Nevertheless, our data suggest a contribution of VEGF to the induction or maintenance of Tregs in the tumor microenvironment. If so, VEGF and VEGFR-2 may be therapeutic targets to improve the efficacy of immunotherapy.

Acknowledgements

This study was supported by General Scientific Research Grants (17390351, 18591440) from the Ministry of Education, Culture, Sports and Technology of Japan. We thank Kaori Nomiyama for skilful technical assistance.

  • Received May 28, 2008.
  • Revision received August 19, 2008.
  • Accepted September 16, 2008.
  • Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

References

  1. ↵
    1. Stearns ME,
    2. Garcia FU,
    3. Fudge K,
    4. Rhim J,
    5. Wang M
    : Role of interleukin 10 and transforming growth factor beta 1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice. Clin Cancer Res 5: 711-720, 1999.
    OpenUrlAbstract/FREE Full Text
    1. Morisaki T,
    2. Katano M,
    3. Ikubo A,
    4. Anan K,
    5. Nakamura M,
    6. Nakamura K,
    7. Sato H,
    8. Tanaka M,
    9. Torisu M
    : Immunosuppressive cytokines (IL-10, TGF-beta) genes expression in human gastric carcinoma tissues. J Surg Oncol 63: 234-239, 1996.
    OpenUrlCrossRefPubMed
    1. Mocellin S,
    2. Wang E,
    3. Marincola FM
    : Cytokines and immune response in the tumor microenvironment. J Immunother 24: 392-407, 2001.
    OpenUrlCrossRefPubMed
    1. von Bernstorff W,
    2. Voss M,
    3. Freichel S,
    4. Schmid A,
    5. Vogel I,
    6. Johnk C,
    7. Henne-Bruns D,
    8. Kremer B,
    9. Kalthoff H
    : Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7: 925s-932s, 2001.
    OpenUrlAbstract/FREE Full Text
    1. Zou W
    : Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5: 263-274, 2005.
    OpenUrlCrossRefPubMed
    1. Jarnicki AG,
    2. Lysaght J,
    3. Todryk S,
    4. Mills KH
    : Suppression of antitumor immunity by IL-10 and TGF-beta-producing T-cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T-cells. J Immunol 177: 896-904, 2006.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Bellone G,
    2. Smirne C,
    3. Mauri F A,
    4. Tonel E,
    5. Carbone A,
    6. Buffolino A,
    7. Dughera L,
    8. Robecchi A,
    9. Pirisi M,
    10. Emanuelli G
    : Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival. Cancer Immunol Immunother 55: 684-698, 2006.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Zitvogel L,
    2. Tesniere A,
    3. Kroemer G
    : Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6: 715-727, 2006.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Zou W
    : Regulatory T-cells, tumour immunity and immunotherapy. Nat Rev Immunol 6: 295-307, 2006.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Gajewski TF,
    2. Meng Y,
    3. Harlin H
    : Immune suppression in the tumor microenvironment. J Immunother 29: 233-240, 2006.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Ohm JE,
    2. Carbone DP
    : VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res 23: 263-272, 2001.
    OpenUrlCrossRefPubMed
    1. Lu H,
    2. Shu XO,
    3. Cui Y,
    4. Kataoka N,
    5. Wen W,
    6. Cai Q,
    7. Ruan ZX,
    8. Gao YT,
    9. Zheng W
    : Association of genetic polymorphisms in the VEGF gene with breast cancer survival. Cancer Res 65: 5015-5019, 2005.
    OpenUrlAbstract/FREE Full Text
    1. Kong SY,
    2. Park JW,
    3. Lee JA,
    4. Park JE,
    5. Park KW,
    6. Hong EK,
    7. Kim CM
    : Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients. Hepatology 46: 446-455, 2007.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Heist RS,
    2. Zhai R,
    3. Liu G,
    4. Zhou W,
    5. Lin X,
    6. Su L,
    7. Asomaning K,
    8. Lynch TJ,
    9. Wain JC,
    10. Christiani DC
    : VEGF polymorphisms and survival in early-stage non-small cell lung cancer. J Clin Oncol 26: 856-862, 2008.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Ferrara N,
    2. Alitalo K
    : Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5: 1359-1364, 1999.
    OpenUrlCrossRefPubMed
    1. Folkman J
    : Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27-31, 1995.
    OpenUrlCrossRefPubMed
    1. Saharinen P,
    2. Tammela T,
    3. Karkkainen MJ,
    4. Alitalo K
    : Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol 25: 387-395, 2004.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Linderholm B,
    2. Grankvist K,
    3. Wilking N,
    4. Johansson M,
    5. Tavelin B,
    6. Henriksson R
    : Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. J Clin Oncol 18: 1423-1431, 2000.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Goffin JR,
    2. Talavera JR
    : Overstated conclusions of a pooled analysis of bevacizumab in colon cancer. J Clin Oncol 24: 528-529; author reply 529-530, 2006.
    OpenUrlFREE Full Text
  11. ↵
    1. Sakaguchi S,
    2. Sakaguchi N,
    3. Shimizu J,
    4. Yamazaki S,
    5. Sakihama T,
    6. Itoh M,
    7. Kuniyasu Y,
    8. Nomura T,
    9. Toda M,
    10. Takahashi T
    : Immunologic tolerance maintained by CD25+ CD4+ regulatory T-cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182: 18-32, 2001.
    OpenUrlCrossRefPubMed
    1. Maloy KJ,
    2. Powrie F
    : Regulatory T-cells in the control of immune pathology. Nat Immunol 2: 816-822, 2001.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Coutinho A,
    2. Hori S,
    3. Carvalho T,
    4. Caramalho I,
    5. Demengeot J
    : Regulatory T-cells: the physiology of autoreactivity in dominant tolerance and “quality control” of immune responses. Immunol Rev 182: 89-98, 2001.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Curiel TJ,
    2. Coukos G,
    3. Zou L,
    4. Alvarez X,
    5. Cheng P,
    6. Mottram P,
    7. Evdemon-Hogan M,
    8. Conejo-Garcia J R,
    9. Zhang L,
    10. Burow M,
    11. Zhu Y,
    12. Wei S,
    13. Kryczek I,
    14. Daniel B,
    15. Gordon A,
    16. Myers L,
    17. Lackner A,
    18. Disis ML,
    19. Knutson KL,
    20. Chen L,
    21. Zou W
    : Specific recruitment of regulatory T-cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10: 942-949, 2004.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Ormandy LA,
    2. Hillemann T,
    3. Wedemeyer H,
    4. Manns MP,
    5. Greten TF,
    6. Korangy F
    : Increased populations of regulatory T-cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65: 2457-2464, 2005.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Miller AM,
    2. Lundberg K,
    3. Ozenci V,
    4. Banham AH,
    5. Hellstrom M,
    6. Egevad L,
    7. Pisa P
    : CD4+CD25high T-cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol 177: 7398-7405, 2006.
    OpenUrlAbstract/FREE Full Text
    1. Kono K,
    2. Kawaida H,
    3. Takahashi A,
    4. Sugai H,
    5. Mimura K,
    6. Miyagawa N,
    7. Omata H,
    8. Fujii H
    : CD4+CD25high regulatory T-cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55: 1064-1071, 2006.
    OpenUrlCrossRefPubMed
    1. Ling KL,
    2. Pratap SE,
    3. Bates GJ,
    4. Singh B,
    5. Mortensen NJ,
    6. George BD,
    7. Warren BF,
    8. Piris J,
    9. Roncador G,
    10. Fox SB,
    11. Banham AH,
    12. Cerundolo V
    : Increased frequency of regulatory T-cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7: 7, 2007.
    OpenUrlPubMed
  16. ↵
    1. Beyer M,
    2. Kochanek M,
    3. Giese T,
    4. Endl E,
    5. Weihrauch MR,
    6. Knolle PA,
    7. Classen S,
    8. Schultze JL
    : In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T-cells in patients with multiple myeloma. Blood 107: 3940-3949, 2006.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Nomura T,
    2. Sakaguchi S
    : Naturally arising CD25+CD4+ regulatory T-cells in tumor immunity. Curr Top Microbiol Immunol 293: 287-302, 2005.
    OpenUrlPubMed
  18. ↵
    1. Onizuka S,
    2. Tawara I,
    3. Shimizu J,
    4. Sakaguchi S,
    5. Fujita T,
    6. Nakayama E
    : Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59: 3128-3133, 1999.
    OpenUrlAbstract/FREE Full Text
    1. Shimizu J,
    2. Yamazaki S,
    3. Sakaguchi S
    : Induction of tumor immunity by removing CD25+CD4+ T-cells: a common basis between tumor immunity and autoimmunity. J Immunol 163: 5211-5218, 1999.
    OpenUrlAbstract/FREE Full Text
    1. Golgher D,
    2. Jones E,
    3. Powrie F,
    4. Elliott T,
    5. Gallimore A
    : Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 32: 3267-3275, 2002.
    OpenUrlCrossRefPubMed
    1. Jones E,
    2. Dahm-Vicker M,
    3. Simon A K,
    4. Green A,
    5. Powrie F,
    6. Cerundolo V,
    7. Gallimore A
    : Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2: 1, 2002.
    OpenUrlPubMed
    1. Sutmuller RP,
    2. van Duivenvoorde LM,
    3. van Elsas A,
    4. Schumacher TN,
    5. Wildenberg ME,
    6. Allison JP,
    7. Toes RE,
    8. Offringa R,
    9. Melief CJ
    : Synergism of cytotoxic T-lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T-cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T-lymphocyte responses. J Exp Med 194: 823-832, 2001.
    OpenUrlAbstract/FREE Full Text
    1. Yu P,
    2. Lee Y,
    3. Liu W,
    4. Krausz T,
    5. Chong A,
    6. Schreiber H,
    7. Fu YX
    : Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201: 779-791, 2005.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Ko K,
    2. Yamazaki S,
    3. Nakamura K,
    4. Nishioka T,
    5. Hirota K,
    6. Yamaguchi T,
    7. Shimizu J,
    8. Nomura T,
    9. Chiba T,
    10. Sakaguchi S
    : Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T-cells. J Exp Med 202: 885-891, 2005.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Beyer M,
    2. Schultze J L
    : Regulatory T-cells in cancer. Blood 108: 804-811, 2006.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Baek JH,
    2. Jang JE,
    3. Kang CM,
    4. Chung HY,
    5. Kim ND,
    6. Kim KW
    : Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene 19: 4621-4631, 2000.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Morisaki T,
    2. Matsumoto K,
    3. Onishi H,
    4. Kuroki H,
    5. Baba E,
    6. Tasaki A,
    7. Kubo M,
    8. Nakamura M,
    9. Inaba S,
    10. Yamaguchi K,
    11. Tanaka M,
    12. Katano M
    : Dendritic cell-based combined immunotherapy with autologous tumor-pulsed dendritic cell vaccine and activated T-cells for cancer patients: rationale, current progress, and perspectives. Hum Cell 16: 175-182, 2003.
    OpenUrlPubMed
  23. ↵
    1. Baecher-Allan C,
    2. Brown JA,
    3. Freeman GJ,
    4. Hafler DA
    : CD4+CD25high regulatory cells in human peripheral blood. J Immunol 167: 1245-1253, 2001.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Li B,
    2. Lalani AS,
    3. Harding TC,
    4. Luan B,
    5. Koprivnikar K,
    6. Huan Tu G,
    7. Prell R,
    8. VanRoey MJ,
    9. Simmons AD,
    10. Jooss K
    : Vascular endothelial growth factor blockade reduces intratumoral regulatory T-cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin Cancer Res 12: 6808-6816, 2006.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Karkkainen MJ,
    2. Petrova TV
    : Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19: 5598-5605, 2000.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Olsson AK,
    2. Dimberg A,
    3. Kreuger J,
    4. Claesson-Welsh L
    : VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7: 359-371, 2006.
    OpenUrlCrossRefPubMed
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Anticancer Research: 29 (3)
Anticancer Research
Vol. 29, Issue 3
March 2009
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The Contribution of Vascular Endothelial Growth Factor to the Induction of Regulatory T-Cells in Malignant Effusions
JUNJI WADA, HIROYUKI SUZUKI, RYOUTA FUCHINO, AKIO YAMASAKI, SHUNTARO NAGAI, KOUSUKE YANAI, KENICHIRO KOGA, MASAFUMI NAKAMURA, MASAO TANAKA, TAKASHI MORISAKI, MITSUO KATANO
Anticancer Research Mar 2009, 29 (3) 881-888;

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The Contribution of Vascular Endothelial Growth Factor to the Induction of Regulatory T-Cells in Malignant Effusions
JUNJI WADA, HIROYUKI SUZUKI, RYOUTA FUCHINO, AKIO YAMASAKI, SHUNTARO NAGAI, KOUSUKE YANAI, KENICHIRO KOGA, MASAFUMI NAKAMURA, MASAO TANAKA, TAKASHI MORISAKI, MITSUO KATANO
Anticancer Research Mar 2009, 29 (3) 881-888;
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