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Increase of Regulatory T Cells in the Peripheral Blood of Cancer Patients¹

Institute for Biomedical Aging Research, Austrian Academy of Sciences, 6020 Innsbruck [A. M. W., B. G-L.], and Division of Hematology and Oncology, Internal Medicine, Leopold-Franzens University of Innsbruck, 6020 Innsbruck [D. W., M. S., G. G., E. G.], Austria

	ABSTRACT

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Purpose: T cells constitutively expressing both CD4 and CD25are essential for maintenance of self-tolerance and therefore have been referred to as regulatory T cells (Treg). Experimental tumor models in mice revealed that Tregs are potent inhibitors of an antitumor immune response. The current study was designed to determine whether cancer patients exhibit an expanded Treg pool.

Experimental Design: The frequency of Tregs in the peripheral blood of 42 patients suffering from epithelial malignancies and from 34 healthy controls was determined by flow cytometry. The immunoregulatory properties of CD4⁺CD25⁺ and CD4⁺CD25^- T cells were characterized by proliferation and suppression assays. Cocultures with natural killer (NK) cells were performed to determine the impact of Tregs on NK-mediated cytotoxicity.

Results: Patients with epithelial malignancies show an increase of CD4⁺CD25⁺ T cells in the peripheral blood with characteristics of Tregs, i.e., they are CD45RA^-, CTLA-4⁺, and transforming growth factor ß⁺. Notably, CD4⁺ T cells from cancer patients are characterized by an impaired proliferative capacity, which is restored to the extend of CD25-depleted CD4⁺ T cells from control persons by prior removal of CD25⁺ T cells. In contrast to CD4⁺CD25^- T cells, isolated CD4⁺CD25⁺ T cells from cancer patients were anergic towards T cell receptor stimulation. In addition, CD4⁺CD25⁺ T cells suppressed the proliferation of CD4⁺CD25^- T cells. When cultured together with CD56⁺ NK-cells, CD4⁺CD25⁺ T cells from cancer patients effectively inhibited NK-cell-mediated cytotoxicity.

Conclusions: Thus, we provide evidence of an increased pool of CD4⁺CD25⁺ regulatory T cells in the peripheral blood of cancer patients with potent immunosuppressive features. These findings should be considered for the design of immunomodulatory therapies such as dendritic cell vaccination.

	Introduction

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The emergence of a tumor results from the disruption of cell growth regulation as well as from failure of the host to provoke a sufficient immunological antitumor response. Indeed, most cancer patients do not develop a satisfactory immunological antitumor response, implicating the existence of tumor-specific immune evasion strategies (1) . Until now, several mechanisms have been described. The metastatic growth of tumors has been shown to be associated with a loss of MHC I expression and of other proteins involved in the processing of antigenic peptides (i.e., TAP1), thereby down-regulating the presentation of T cell activating epitopes (2) . Other effective strategies are the secretion of tumor-derived immunosuppressive factors, such as IL³ -10 and TGF-ß (3) or the induction of immunotolerance against tumor-specific antigens (4) . Recently, the existence of a CD4⁺CD25⁺CD45RA^- Treg population has been described in rodents and in humans (5, 6, 7, 8, 9) . In healthy humans, this population accounts for 5–10% of peripheral CD4⁺ T cells. The observation that Treg-depleted mice develop a broad range of autoimmunopathies suggests that this T cell subset plays a crucial role for the control of T cell-mediated autoimmunity (5) . Notably, removal of regulatory T cells can also evoke effective antitumor immunity in mice injected with syngeneic cancer cells (5) . Thus, we hypothesized that elevation of Tregs may down-regulate tumor-specific immunity. We therefore performed the current study to determine whether cancer patients exhibit an expanded Treg pool.

	Materials and Methods

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Patients.
After having obtained informed consent, heparinized blood samples were collected from 34 healthy volunteers and 42 patients with malignant tumors. Information regarding patient history and tumor stage was recorded. The following tumor entities were included (Table 1) : lung cancer (n = 16, 11 in stage IV, 2 in stage IIIa, 2 in stage IIIb, and 1 in stage I); breast cancer (n = 6, 1 in stage IV, 1 in stage IIIb, 1 in stage II, and 3 in stage I); colorectal cancer (n = 9, 3 in stage IV, 1 in stage III, 2 in stage II, and 3 in stage I); gastric cancer (n = 3, 1 in stage IV, 1 in stage IIIa, and 1 in stage Ib); pancreatic cancer (n = 2 in stage IV); gallbladder carcinoma (n = 2 in stage IV); esophageal cancer (n = 1 in stage IV); epipharyngeal cancer (n = 1 in stage IV); cervical cancer (n = 1 in stage IV); and ovarian cancer (n = 1 in stage IV). The mean age of the cancer patients was 66.3 ± 10.4 years, the corresponding healthy controls had a mean age of 52.3 ± 22.4 years. Increasing age has no impact on relative and absolute numbers of Tregs in the peripheral blood (unpublished results).

Flow Cytometric Analysis.
To determine the regulatory cell phenotype, three- and four-color flow cytometry of whole blood or isolated CD4⁺CD25⁺ and CD4⁺CD25^- T cells was performed using the following antibodies: anti-CD4; anti-CD11a; anti-CD25; anti-CD28; anti-CD31; anti-CD45RA; anti-CD62L; anti-CD69; anti-CD95; anti-CD154; anti-CTLA-4; and IgG1-isotype control (either FITC-, PE-, peridin chlorophyll protein- or adenomatous polyposis coli-conjugated, all purchased from BD PharMingen). For whole blood stainings, 50 µl of whole blood were incubated with appropriate amounts of fluorochrome-labeled Abs in the dark at room temperature for 30 min, washed once, and analyzed. Isolated T cells were stained with titrated amounts of Ab and washed once. Anti-TGF-ß mAb (R&D, unconjugated) was detected by a PE- labeled rabbit-antimouse mAb (Dako), according to the manufacturer’s instructions. Cytoplasmatic bcl-2 was determined by intracellular flow cytometry as follows. After surface staining and lysing of RBCs, cells were permeabilized using Cytofix/Cytoperm solution (BD PharMingen), stained with FITC-anti-bcl-2 mAb (Dako) for 30 min at room temperature and washed once. To compare the phenotype of recently in vitro activated T cells with the CD4⁺CD25⁺ population, 1 ml of whole blood was stimulated with 10 ng/ml PMA (Sigma) and 0.5 µg/ml Ionomycin (Sigma) for 48 h before FACS analysis. Flow cytometry was performed on a Becton Dickinson FACSCalibur or FACScan and CellQuest software was used for analysis

Quantification of Absolute Cell Numbers.
Absolute cell numbers were determined using TruCOUNT Tubes (BD PharMingen) and a lyse-no-wash method according to the manufacturer’s instructions. In brief, 50 µl of whole blood were stained for CD3, CD4, CD25, and CD45RA, lysed with 450 µl of FACS lysing solution (BD PharMingen), and directly analyzed on the flow cytometer. Total cell numbers were calculated by gating on reference beads.

Cytokine Assays.
For intracellular analysis of cytokine production anti-IL-4-PE, anti-IL-10-PE, and anti-IFN--FITC mAbs as well as the corresponding isotype-controls were used (all purchased from BD PharMingen). Briefly, 10⁶ isolated CD4⁺CD25⁺ and CD4⁺CD25^- T cells were activated with 10 ng/ml PMA, 0.5 µg/ml Ionomycin, and 1 µl/ml GolgiPlug (BD PharMingen) for 4 h. Cells were washed, fixed and permeabilized (Cytofix/Cytoperm solution; BD PharMingen), and stained with titrated amounts of cytokine-specific antibodies.

Cell Isolation and Generation of DCs.
Either CD4⁺ or CD56⁺ cells were purified from peripheral blood by Ficoll-Paque density gradient centrifugation followed by isolation with immunomagnetic beads (Miltenyi Biotech). In the case of isolated CD4⁺ T cells, CD4 beads were detached and stained with anti-CD25 beads, followed by positive and negative selection (purity of CD4⁺CD25⁺ population: >85%; CD4⁺CD25^- population: >98%, CD56⁺ population: >98%).

DCs were generated from peripheral blood of healthy volunteers as described previously (10) . In brief, PBMCs were isolated by Ficoll density gradient centrifugation. Monocytes were isolated by plastic adherence and cultured in RPMI 1640 supplemented with 10% human serum, 800 units/ml granulocyte macrophage colony-stimulating factor, and 1000 units/ml IL-4. On day 7, nonadherent cells were transferred to fresh 6-well plates and 10 ng/ml IL-1ß, 10 ng/ml tumor necrosis factor , 1000 units/ml IL-6, and 1 µg/ml prostaglandin E₂ were added for maturation. For allogeneic stimulation, mature DCs were harvested at day 9 and irradiated (40 Gy).

Expansion of CD4⁺CD25⁺ and CD4⁺CD25^- Cells.
Isolated cells were cultured in RPMI 1640 supplemented with 10% FCS and 1% penicillin/streptomycin. Isolated T cells (10⁶) were stimulated with 100 units/ml IL-2 and 20 ng/ml anti-CD3 mAb (OKT3; Sigma) in the presence of irradiated (40 Gy) autologous PBMC (10⁶/ml). IL-2 was supplemented every 3 days, and cells were restimulated with OKT3 and feeder-PBMCs every 7 days. The expansion of CD4⁺CD25⁺ T cells and the respective CD4⁺CD25^- T cells was quantified by counting cell numbers on days 0, 5, 10, 15, and 20 using trypan blue exclusion for the calculation of absolute cell numbers. Unless otherwise indicated, expanded CD4⁺CD25⁺ T cells were cultured for 10 days.

Proliferation Assays.
CD4⁺CD25⁺ or CD4⁺CD25^- cells (10⁵) were cultured in the presence of 10⁵-irradiated allogeneic DCs or stimulated with plate-bound anti-CD3 mAb (2 µg/ml). After 4 days, [³ H]thymidine was added for an additional 16 h of culture before the incorporation of [³ H]thymidine was assessed. To determine whether the increase of CD4⁺CD25⁺ T cells is also of functional importance, we performed proliferation assays using 10⁵ immunomagnetically selected CD4⁺ T cells from cancer patients and healthy controls either before or after depletion of CD25⁺ T cells (CD4⁺CD25^- T cell fraction).

Suppression Assays.
To determine regulatory properties, cocultures of 5 x 10⁴ CD4⁺CD25⁺ (freshly isolated or expanded) and CD4⁺CD25^- T cells from cancer patients that were stimulated either by allogeneic DCs in a ratio of 1:1:1 or by plate-bound anti-CD3 mAb (2 µg/ml) were performed. Proliferation was measured after 4 days by [³ H]thymidine incorporation.

Cytotoxicity Assays.
The assay was performed as previously described (11) with slight modifications. In brief, 2 x 10⁶ CD56-selected NK effector cells were preincubated with equal numbers of CD4⁺CD25^-, CD4⁺CD25⁺ T cells or medium alone at 37°C for 2 h. PKH-labeled (Sigma) K562 cells were used as target cells. After incubation, 5 x 10⁴ target cells were added and cultured for additional 4 h. Propidium iodide (10 µg) was added immediately before the FACS analysis. The specific lysis was calculated as total lysis - spontaneous lysis.

	Results

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Quantification of Relative and Absolute CD4⁺CD25⁺ T Cell Numbers.
In healthy controls (n = 34), the mean percentage of CD4⁺CD25⁺CD45RA^- cells in the peripheral blood was 4.7 ± 0.5% of all CD4⁺ T cells. In contrast, peripheral blood of cancer patients (n = 42) exhibited a 2.5-fold increase in CD4⁺CD25⁺CD45RA^- T cells (12.5 ± 0.9% of the CD4⁺ population), which is highly significant (P 0.001) as compared with healthy controls (Fig. 1, A and C) . Patient characteristics, tumor entities, and stages as well as the respective percentage of CD4⁺CD25⁺CD45RA^- T cells are given in Table 1 . The number of CD4⁺CD25⁺CD45RA^- T cells did not correlate with either tumor stage or tumor type (data not shown). Quantification of absolute cell counts of 10 cancer patients and 10 control persons revealed that not only the percentage but also the total cell number of CD4⁺CD25⁺CD45RA^- T cells per µl was significantly increased in cancer patients (P 0.01) as indicated in Fig. 1B .

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Cancer patients show a significant increase in CD4+CD25+ T cells. A, the percentage of CD4+CD25+CD45RA- T cells in the peripheral blood of 42 cancer patients () was determined by flow cytometry and compared with 34 healthy controls (). The values are given as mean value ± SE. *, P 0.001 versus healthy control (Student’s t test). B, absolute cell counts of CD4+CD25+CD45RA- T cells of cancer patients () and healthy controls () as mean value ± SE. *, P 0.01 (Student’s t test). C, a representative staining for CD25 and CD45RA of CD4+-gated T cells is shown for one cancer patient and one healthy control.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Increased inhibition of CD4+ T cell proliferation by CD4+CD25+ T cells of cancer patients. The proliferative response of freshly isolated CD4+ T cells of 7 cancer patients and 3 healthy controls activated with plate-bound OKT3. [3H]thymidine incorporation was determined in triplicates before and after depletion of CD25+ T cells as well as of the isolated CD4+CD25+ T cells. *, P 0.01 for CD4+ T cells versus CD25-depleted T cells. Proliferation of CD25-depleted CD4 T cells was considered as 100%. Notably, total proliferation rates of CD4+CD25- T cells from both groups reached comparable levels between 17,000 and 40,000 cpm. The values are given as mean value ± SEM.

View larger version (53K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. CD4+CD25+ T cells express distinct surface markers as compared with activated T cells. A, fresh (top panel) and PMA-activated (bottom panel) whole blood of cancer patients was stained for CD4, CD25, CD45RA, and CD69. One representative staining is shown for three independent experiments.

View larger version (48K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. CD4+CD25+ T cells from cancer patients exhibit a Treg-phenotype. A, isolated and expanded CD4+CD25+ (dark line) and CD4+CD25- T cells (light line) were stained with anti-CD28, anti-CD95, anti-CD154, or the corresponding isotype control (dashed line). One representative result is shown for three independent experiments. B, surface expression of CTLA-4 and TGF-ß and intracellular staining of bcl-2 of isolated CD4+CD25+ T cells (dark line), CD4+CD25- T cells (light line), or the corresponding isotype control (dashed line). One representative result is shown for at least three independent experiments. C, intracellular cytokine production of CD4+CD25+ (dark line) and CD4+CD25- T cells (light line) was determined by anti-IL4, anti-IL-10, and anti-IFN- mAbs after 4 h of PMA stimulation. The isotype control staining is shown by the dashed line.

Proliferative Capacity in Response to Allogeneic DCs and Polyclonal TCR Stimulation.
Functional analysis revealed that Tregs are anergic to TCR stimulation (i.e., by anti-CD3; Ref. 6 ). However, addition of exogenous IL-2 allowed the propagation of CD4⁺CD25⁺ T cells isolated from peripheral blood of cancer patients. Fig. 5 shows typical expansion curves of the two cell populations over a time period of 20 days from a cancer patient and a control person. In vitro expanded CD4⁺CD25⁺ T cells of cancer patients failed to proliferate in response to allogeneic DCs when exogenous IL-2 was removed (data not shown). The proliferation assays were additionally performed with anti-CD3 mAb stimulation to exclude the potential selection of an alloreactive CD4⁺CD25⁺ subpopulation upon stimulation with allogeneic DCs. Again, CD4⁺CD25⁺ T cells were anergic, whereas the CD4⁺CD25^- population showed a marked proliferative response to anti-CD3 stimulation (Fig. 6, A and B) . There is no difference between cancer patients as compared with healthy control persons in terms of the proliferative capacitiy of Tregs (Fig. 5 and Fig. 6, A and B ). Moreover, Treg-expansion failed to modulate the anergic state of CD4⁺CD25⁺ T cells from both groups (Fig. 6, A and B) .

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Expandability of CD4+CD25- and CD4+CD25+ T cells grown in the presence of OKT3 and IL-2. Expansion curves of CD4+CD25+ (•) and CD4+CD25- () T cells over a time span of 20 days from one cancer patient and one control person are shown. Freshly isolated CD4+CD25+ and CD4+CD25- T cells were stimulated with OKT3 and IL-2 at day 1. IL-2 was added every 3 days, and cells were restimulated with OKT3 every 7 days. Total cell numbers were determined by trypan blue exclusion in triplicates. The values are given as mean value ± SEM. Similar results were obtained in three independent experiments. One representative example is shown for 3 independent experiments.

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Fig. 6. In vitro expanded CD4+CD25+ T cells from cancer patients show an equal suppressive efficacy as compared with control CD4+CD25+ T cells. Freshly isolated and for 10 days expanded, CD4+CD25+ and CD4+CD25- T-cells from (A) healthy control people (n = 3) and (B) cancer patients (n = 14) were activated with plate-bound OKT3 and tested for their ability to proliferate either alone or in cocultures of CD4+CD25+ together with CD4+CD25- T cells (ratio of 1:1). Proliferation was determined in triplicate cultures by [3H]thymidine incorporation, and proliferation of CD4+CD25- T cells was considered as 100% (mean ± SEM). *, P 0.05 for CD4+CD25- versus CD4+CD25+/CD4+CD25- for healthy controls after expansion and cancer patients before and after expansion (Student’s t test).

Inhibition of NK Cell-mediated Cytotoxicity.
NK cells are an effective part of the innate antitumor response (13) . To determine the suppressive effect of CD4⁺CD25⁺ T cells on in vitro cytotoxicity against tumor cells, we performed cytotoxicity assays with the NK target cell line K562. The latter was cultured together with CD56-selected NK cells in a ratio of 1:40 for 4 h. Preincubation of the effector cells together with CD4⁺CD25⁺ T cells for 2 h (ratio 1:1) significantly reduced NK cell-mediated target cell lysis (P 0.01). In contrast, after preincubation of NK cells with CD4⁺CD25^- T cells, only a slight decrease of NK cell-mediated cytolysis could be detected (Fig. 7) compared with NK cells, which were incubated for 2 h in medium alone. These results demonstrate that Tregs from cancer patients are effective inhibitors of NK cell-mediated antitumor responses.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Fig. 7. CD4+CD25+ from cancer patients effectively inhibit NK cell-mediated cytotoxicity. NK effector cells (2 x 106) were preincubated for 2 h with either CD4+CD25+ () or CD4+CD25- () T cells in a ratio of 1:1 before 5 x 104 K562 target cells were added for additional 4 h (E:T ratio, 40:1). As control, 2 x 106 NK cells were cultured for 4 h with 5 x 104 target cells after 2 h of preincubation with medium alone (). The mean value ± SEM of specific lysis from three independent experiments of 3 patients was calculated as total lysis - spontaneous lysis. *, P 0.01 (Student’s t test).

	Discussion

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In summary, our observations provide additional insight into the regulatory mechanisms responsible for immunosuppression in human cancer, which may facilitate local tumor growth and metastasis. Hematogenic metastasis often represents the fatal step during the course of malignancy, which may be significantly enhanced by the suppression of blood-borne immunosurveillance mechanisms. Moreover, Tregs may also negatively impact the effectiveness of immunotherapies such as tumor-targeted monoclonal antibodies (e.g., trastuzumab, rituximab). Finally, depletion of Tregs may become a successful anticancer strategy. In fact, in a mouse model, the efficacy of a therapeutic vaccine against melanoma was substantially improved by depletion of Tregs before challenging the animals with granulocyte colony-stimulating factor- or IFN--producing tumor cells (15 , 20) . In conclusion, manipulation of Tregs in terms of their frequency and functional activity should be added to the therapeutic armentarium for enhancing tumor immunity in humans.

	ACKNOWLEDGMENTS

 
We thank Dr. Alice Markl for the sample collection and Brigitte Jenewein for her excellent technical assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The study was funded by the Austrian Federal Ministry of Science and Transport Grant az 70.062/2-PR/4/99 and the Tiroler Verein zur Förderung der Krebsforschung.

² To whom requests for reprints should be addressed, at Rennweg 10, 6020 Innsbruck, Austria. Phone: 43-512-58391913; Fax: 43-512-5839198; E-mail: Maria.Wolf{at}oeaw.ac.at

³ The abbreviations used are: IL, interleukin; TGF, transforming growth factor; Treg, regulatory T cell; PE, phycoerythrin; Ab, antibody; mAb, monoclonal antibody; PMA, phorbol 12-myristate 13-acetate; FACS, fluorescence-activated cell sorting; DC, dendritic cell; NK, natural killer; PBMC, peripheral blood mononuclear cell; TCR, T-cell receptor.

Received 5/14/02; revised 8/30/02; accepted 9/ 6/02.

	REFERENCES

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