| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell, Tumor, and Stem Cell Biology |
Departments of 1 Internal Medicine and Molecular Science and 2 Clinical Pathology, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya-shi, Aichi, Japan
Requests for reprints: Takashi Ishida, Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. Phone: 81-52-853-8216; Fax: 81-52-852-0849; E-mail: itakashi{at}med.nagoya-cu.ac.jp.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We have recently developed a novel chimeric monoclonal antibody (mAb), KM2760, which binds specifically to CCR4 (12, 13), and we are currently preparing for phase I and II clinical trials of administration of this antibody in patients with CCR4-positive T-cell lymphomas (14, 15). We have also reported that FOXP3 mRNA was expressed in CD4+CCR4+ T cells at a level nearly comparable to that in CD4+CD25+ T cells, and that KM2760 treatment reduced the FOXP3 mRNA expression level in parallel with the CCR4 mRNA level in PBMC obtained from healthy volunteers (12). These observations prompted us to hypothesize that KM2760 could be used as a novel strategy for treatment of patients with HL. The antibody could induce an effective antitumor immunity by reducing the concentration of CCR4-positive Treg cells in the HL tumor cell environment. In the present study, we also test in vitro the ability of KM2760 to overcome the immunosuppressive environment around HL cells by measuring the antibody effect on migratory cells induced by the supernatants of the HL cell lines.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Antibodies. Mouse anti-human TARC/CCL17 mAb (clone 54026.11) and mouse anti-human MDC/CCL22 mAb (clone 57226.11) were purchased from R&D Systems, Inc. (Minneapolis, MN). FITC-conjugated mouse anti-human CCR4 mAb (FITC-KM2160) was previously described (14). Allophycocyanin-conjugated antihuman CD8 mAb (clone RPA-T8) and its allophycocyanin-conjugated isotype control mAb were purchased from eBioscience (San Diego, CA). Peridinin chlorophyll protein (PerCP)-conjugated antihuman CD4 mAb (clone SK3), phycoerythrin (PE)-conjugated antihuman CD25 mAb (clone M-A251), PE-conjugated anti-CCR4 mAb (clone 1G1), and their PerCP- and PE-conjugated isotype control mAbs, and FITC-conjugated isotype control mAb for KM2160 were purchased from BD Biosciences (San Jose, CA). The chimeric anti-CCR4 mAb (KM2760) was previously described (12, 13). Rituximab (16), which is an isotype-matched mAb with KM2760, was kindly provided by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan).
Human PBMC and flow cytometry analysis. Human PBMC were isolated from healthy volunteers using Ficoll-Paque (Pharmacia, Uppsala, Sweden). The volunteers gave informed written consent before the sampling procedure according to the Declaration of Helsinki. The PBMC were cultured in RPMI 1640 containing 0.5% bovine serum albumin (BSA) in a 10-cm plastic culture dish for 1 hour to allow monocytes to adhere and the nonadherent cells were recovered and used as human peripheral blood lymphocytes (PBL). CD4-positive or -negative cells were isolated from human PBMC using the CD4+ T Cell Biotin-Antibody Cocktail Human (Miltenyi Biotec, Bergisch Gladbach, Germany) and Anti-Biotin MicroBeads (Miltenyi Biotec) according to the instructions of the manufacturer.
In another experiment, PBMC obtained from 15 healthy adult volunteers were incubated in RPMI 1640 supplemented with heat-inactivated 10% fetal bovine serum (FBS) at 37°C, 5% CO2 for 12 hours with KM2760 at a concentration of 10 µg/mL per well in a 12-well culture plate (1.5 x 107 cells/3 mL). A control culture was incubated without KM2760 in the same manner. At the end of the culture period, the cells were washed twice in PBS and assessed by two-color flow cytometry analysis using PerCP-conjugated anti-CD4 mAb and PE-conjugated anti-CCR4 mAb (1G1) or PerCP- and PE-conjugated isotype control mAbs. Rituximab, which is an isotype-matched mAb control for KM2760, was incubated with the PBMC in the same manner as KM2760.
Chemoattractant. HDLM-2, KM-H2, L-1236, L-428, L-540, KARPAS-299, and SU-DHL-1 were suspended in RPMI 1640 containing 0.5% BSA at 3 x 105 cells/mL. The cells were cultured at 37°C, 5% CO2 for 96 hours, then each supernatant was collected and filtered through 0.22-µm pores to remove the debris and then used as chemoattractant. The RPMI 1640 containing 0.5% BSA alone was treated in the same manner and the supernatant was used as control chemoattractant. The TARC/CCL17 and MDC/CCL22 concentrations in each supernatant were determined by an ELISA using the Human TARC/CCL17 or MDC/CCL22 Immunoassay Kit (R&D Systems), respectively, according to the instructions of the manufacturer. All expressed values were averages of duplicate experiments. Recombinant human (rh)-TARC/CCL17 (R&D Systems) and/or rh-MDC/CCL22 (R&D Systems) were used as control chemoattractants.
Chemotaxis assay. Human PBL (1 x 106) suspended in 200 µL of RPMI 1640 containing 0.5% BSA were placed in the upper wells of a Chemotaxicell chemotaxis chamber with a 3-µm pore membrane (Kurabo, Osaka, Japan). The lower wells contained the chemoattractants (500 µL/well). In some experiments, anti-TARC/CCL17 mAbs and/or anti-MDC/CCL22 mAbs were added to the lower wells at final concentrations of 50 µg/mL each or KM2760 was added to the upper wells at a final concentration of 10 µg/mL. After 4 hours of incubation at 37°C, 5% CO2, cells that migrated into the lower wells were recovered and stained with PerCP-anti-CD4, allophycocyanin-anti-CD8, PE-anti-CD25, and FITC-anti-CCR4 (KM2160) and their isotype-matched mAbs. After staining, a predetermined number of standard beads (Flow-Count, Beckman coulter, Fullerton, CA) were added and the number of cells in each stained cell group was counted using FACSCalibur flow cytometer with the aid of CellQuest software (BD Biosciences) according to the instructions of the manufacturer. All expressed values were averages of triplicate experiments ± SD.
Cell proliferation and IFN-
production assay. Human CD4-positive cells (1 x 106) suspended in 200 µL of RPMI 1640 containing 0.5% BSA were placed in the upper wells of a Chemotaxicell chemotaxis chamber with a 3-µm pore membrane; the lower wells contained the chemoattractants (500 µL/well). The CD4+ cells placed in the upper wells and each migratory cell population in the lower wells were assessed for their proliferation and IFN- production activity in response to T-cell receptor (TCR) stimulation in the presence of autologous antigen-presenting cells (APC). Autologous CD4-negative cells obtained from PBMC were irradiated (25 Gy) and used as APC. The CD4+ cells (0.75 x 104) placed in the upper wells or migratory cells (0.75 x 104) in the lower wells were cultured in the presence of 3.75 x 104 APCs and soluble anti-CD3 mAb (clone Hit3a, BD Biosciences) at a final concentration of 20 ng/mL in RPMI 1640 supplemented with heat-inactivated 10% FBS for 96 hours in a total volume of 150 µL/well (U-bottomed 96-well plate). [3H]Thymidine diluted in RPMI 1640 supplemented with heat-inactivated 10% FBS (0.5 µCi/50 µL/well) was added to each well for the last 20 hours of culture and incorporation of the [3H]thymidine (cpm) was measured as an indicator of cell proliferation using a scintillation counter (Perkin-Elmer, Wellesley, MA). All expressed values were averages of triplicate experiments ± SD. For measurement of IFN- production, 50 µL of RPMI 1640 supplemented with heat-inactivated 10% FBS, instead of [3H]thymidine, were added to each well for the last 20 hours and the supernatants were collected. IFN- in the supernatant was measured by a Human IFN- ELISA Kit (BioSource International, Camarillo, CA) according to the instructions of the manufacturer. All expressed values were averages of triplicate experiments ± SD.
In addition, the CD4+ cells placed in the upper wells and each of the migratory cell populations in the lower wells were assessed for their ability to suppress the proliferation and IFN- production activity of the CD4+ cells placed in the upper wells as an effector cell population. The CD4+ cells (0.75 x 104) placed in the upper wells or each migratory cell population (0.75 x 104) was cocultured with the CD4+ cells placed in the upper wells at a ratio of 1:1 in the presence of 3.75 x 104 APCs and soluble anti-CD3 mAb, and each of the cocultured cell populations was assessed for proliferation and IFN- production activity in the same manner.
Double immunostaining. The double immunostaining analysis was done as previously described (17). Briefly, the formalin-fixed, paraffin-embedded sections of lymph node tissues affected by HL were immunostained using mAbs against human CCR4 (KM2160) and human FOXP3 (236A/E7; Abcam plc, Cambridge, United Kingdom). CCR4 protein at the membrane was visualized in brown with 3,3' diaminobenzidine tetrahydrochloride and FOXP3 protein at the nucleus was visualized in blue with tetramethylbenzidine (True Blue, KPL, Gaithersburg, MD). The slides were counterstained with nuclear fast red and mounted.
Statistical analysis. The significance of changes in the proportion of CD4+ T cells in the absence or presence of KM2760 or Rituximab was examined using the Wilcoxon signed-rank test. Data were analyzed with the aid of StatView software (version 5.0, SAS Institute, Cary, NC). In this study, P < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
|
|
|
production activity in response to TCR stimulation in the presence of autologous APC and for their ability to suppress IFN- production activity of the CD4+ cells (Fig. 3B). When the CD4+ cells in the upper wells were stimulated with soluble anti-CD3 mAb in the presence of autologous APC, they produced IFN- at a concentration of 3.2 ± 1.6 pg/mL. On the other hand, when the migratory cells in the lower well induced by the HL cell lines, HDLM-2, L-1236, and L-428, were stimulated in the same manner, they only produced small amounts of IFN- in each well (0.9 ± 0.8, 1.2 ± 0.2, and 0.8 ± 0.7 pg/mL, respectively). The migratory cells in the lower wells induced by 100 ng/mL rh-TARC/CCL17 or 100 ng/mL rh-MDC/CCL22 also produced small amounts of IFN- in each well (1.0 ± 0.0, and 1.1 ± 0.2, respectively; Fig. 3B, left). When the two cell populations were cocultured at a ratio of 1:1 with soluble anti-CD3 mAb in the presence of autologous APC, the migratory cells induced by the HL cell lines HDLM-2, L-1236, and L-428 dramatically suppressed the IFN- production of the CD4+ cells. When the two populations were cocultured at a ratio of 1:1 in the same manner, the migratory cells induced by rh-TARC/CCL17 or rh-MDC/CCL22 also dramatically suppressed the IFN- production of the CD4+ cells (Fig. 3B, right). Double immunostaining analysis for CCR4 and FOXP3 expression in affected lymph nodes obtained from patients with HL. We did double-immunostaining analysis for CCR4 and FOXP3 using affected lymph node tissues obtained from the HL patients. A representative picture from a patient with mixed cellularity HL is shown in Fig. 4 . In this case, nearly 80% of the reactive nontumor lymphocytes surrounding the HL tumor cells expressed CCR4 (visualized in brown) at the membrane and nearly 30% of the CCR4 positive reactive lymphocytes simultaneously expressed FOXP3 (visualized in blue) at the nucleus. Any lymphocyte expressing FOXP3 at the nucleus simultaneously expressed CCR4 at the membrane.
|
|
KM2760-induced inhibition of the migration of CD4+CD25+ T cells. The KM2760-induced inhibition of the migration of CD4+CD25+ T cells was examined via the PBL chemotaxis assay (Fig. 5D). A concentration of 10 µg/mL KM2760 in the upper well partly inhibited the migration of the CD4+CD25+ T cells induced by rh-TARC/CCL17 (41 ± 11%), rh-MDC/CCL22 (55 ± 13%), and the supernatant of HDLM-2 (46 ± 7%). Importantly, KM2760 did not block the interaction between CCR4 and TARC/CCL17 or between CCR4 and MDC/CCL22 (data not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Treg cells exist in a CD4+CD25+ cell subpopulation, and FOXP3 can be specifically expressed in CD4+CD25+ Treg cells and is associated with their development and function (8–11). Notably, we showed here that HL cell lines attracted CD4+CD25+CCR4+ T cells, but CD8+ T cells and ALCL cell lines attracted neither CD4+CD25+CCR4+ T cells nor CD8+ T cells. In addition, most importantly, this is the first report showing that migratory cells, induced by the supernatants of HL tumor cells, are hyporesponsive to TCR stimulation and suppress the activation/proliferation of the effector T cells in an autologous setting. These findings show that the migratory cells induced by HL cells function as Treg cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. Our data thus provide a strong rationale for the ineffective immune clearance of HL cells by the host immune system. We showed here that rh-TARC/CCL17 and rh-MDC/CCL22 exhibited robust chemotactic activity for CD4+CD25+CCR4+ cells and that the migratory cells induced by these two specific ligands for CCR4 also were hyporesponsive to TCR stimulation and suppressed the activation/proliferation of the effector T cells in an autologous setting. Furthermore, antihuman TARC/CCL17 or MDC/CCL22 mAb alone did not fully inhibit the migration of the CD4+CD25+ T cells induced by the supernatant of one of the HL cell lines, HDLM-2, which produced both TARC/CCL17 and MDC/CCL22, whereas both mAbs together almost completely inhibited the migration of the CD4+CD25+ T cells in response to the HDML-2 supernatant. These findings indicate that the migration of CD4+CD25+ Treg cells induced by HDLM-2 was attributable to the interaction between CCR4 expressed on Treg cells and TARC/CCL17 or MDC/CCL22. The double immunostaining analysis for CCR4 and FOXP3 in affected lymph node tissues obtained from the HL patients confirmed the in vitro observations mentioned above. That is to say, HL tumor cells were actually surrounded by a large number of lymphocytes that expressed both CCR4 and FOXP3. In contrast with the results obtained using affected lymph nodes from patients with HL, we have previously reported that in non-tumor-affected reactive lymph nodes, only a small number of interfollicular T cells were positive for CCR4 by immunostaining, and these comprised 3% to 7% of all cells in the paracortex area (14). In affected lymph nodes from patients with HL, any lymphocyte expressing FOXP3 at the nucleus simultaneously expressed CCR4 at the membrane whereas some lymphocytes expressing CCR4 did not express FOXP3. Because the CCR4 is also known to be expressed on Th2 cells (19–22), these reactive CCR4+FOXP3– lymphocytes seem to be Th2 cells, which is consistent with the reports by other investigators that reactive lymphocytes in affected lymph nodes from patients with HL mainly consisted of Th2 cells (23, 24).
Clinical observations by van den Berg et al. (2) also support the present study: tumor cells from HL patients express TARC/CCL17 and reactive lymphocytes surrounding the HL tumor cells express CCR4. A situation similar to that of HL has been shown in another hematologic neoplasm, B-cell chronic lymphocytic leukemia (B-CLL). B-CLL cells produced MDC/CCL22 and attracted CCR4+ T cells (25) and patients with B-CLL showed significantly increased frequencies of CD4+CD25high Treg cells in their peripheral blood CD4+ T cells compared with the healthy individuals (26). Furthermore, Curiel et al. (6) have recently reported that ovarian cancer cells and microenvironmental macrophages produce the MDC/CCL22, which mediates trafficking of CCR4+ Treg cells to the tumor, and that this specific recruitment of CCR4+ Treg cells represents a mechanism by which tumors may gain immune privilege. In addition, Nakayama et al. (27) have recently reported that EBV-infected B cells acquire the ability to produce TARC/CCL17 and MDC/CCL22 and suggested that the production of TARC/CCL17 and MDC/CCL22, which attract CCR4+ Treg cells, may help EBV-infected B cells evade immune surveillance by the host immune system.
The recognition of the importance of Treg cells in HL pathogenesis will allow rational design of more effective treatments. For instance, experimental depletion of Treg cells in mice with tumors improved immune-mediated tumor clearance (28) and enhanced the response to immune-based therapy (29). In addition, a clinical trial of a fully human mAb that blocks CTLA-4 has already established the possibility of effecting substantial tumor destruction, although at the expense of some autoimmunity (30). In the present study, KM2760 treatment significantly reduced the proportion of CD4+CCR4+ T cells in PBMC and CD4+CCR4+ T cells in CD4+ T cells obtained from 15 healthy adult volunteers. We have previously reported that KM2760 induces a robust antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive lymphoma cells but does not induce any complement-dependent cytotoxicity or direct antiproliferation activity (12). Based on these observations, we can therefore conclude that the observed CCR4+ T-cell reduction in a PBMC culture incubated with KM2760 was induced by ADCC. In this situation, natural killer (NK) cells and monocytes in the PBMC play a role as effector cells in the ADCC. We also previously reported that the majority of CD4+CCR4+ T cells exist in a CD25+ subpopulation of PBMC from healthy volunteers (12) and we showed here in the chemotaxis assay that the migratory CD4+ cells induced by HL cells consisted of a large majority of CD25+CCR4+ cells. These observations indicate that the KM2760-induced inhibition of the migration of CD4+CD25+ T cells in the present study was due to KM2760-induced lysis of CD4+CD25+CCR4+ T cells during the 4-hour incubation. Successful treatment of HL patients with KM2760 would require depletion of the CCR4+ Treg cells not only in the periphery but also in the affected lymph nodes. KM2760 should be able to accomplish this in vivo because NK cells or macrophages, which can mediate ADCC, partly constitute the abundant infiltrating nontumor cells in the affected lymph nodes with HL (1, 31). In addition, the Fc region in KM2760 is artificially defucosylated to enhance ADCC by increasing its binding affinity to the Fc receptor on effector cells (12, 13). Collectively, these findings suggest that KM2760 could be used as a novel strategy for treatment of HL patients and function as a novel inducer of effective anticancer immunity by depleting the CCR4+ Treg cells. On the other hand, it was necessary to be alert to possible KM2760-induced autoimmunity, as reported in the anti-CTLA-4 mAb study (30); thus, KM2760 underwent extensive evaluation in cynomolgus monkeys and did not cause any notable acute or chronic clinical toxicity.3
In conclusion, we have clarified here how the abundant nontumor cells in the environment of a small number of HL tumor cells contribute to the immunopathogenesis. The CD4+CD25+CCR4+ Treg cells migrate to the HL cells in a process mediated by the chemokines TARC/CCL17 and/or MDC/CCL22, which are produced by the HL cells and are capable of suppressing the host antitumor response. We have also shown here that KM2760 can deplete the CCR4+ T cells and inhibit the migration of CD4+CD25+ T cells induced by the HL cells. In this connection, it is also relevant to note that Rituximab, a chimeric anti-CD20 mAb, combined with the chemotherapy regimen, cyclophosphamide-doxorubicin-vincristine-prednisone, has changed the standard therapy in elderly patients with diffuse large B-cell lymphoma (16). Now, an anti-CCR4 mAb could be an ideal treatment modality for patients with CCR4+ neoplasms (14, 15, 32) and could also be used as a novel strategy for treatment of a variety of other diseases, such as HL, B-CLL, ovarian cancer, and EBV-associated disease, to overcome the suppressive effect of CCR4+ Treg cells on the host immune response to tumor or virus-infected cells. Especially in HL, therapy with an anti-CCR4 mAb combined with tumor-specific CTLs (33, 34), which are often impaired by Treg cells (35), will offer a novel treatment approach worthy of pursuit. Furthermore, combination treatment with this mAb and conventional chemotherapy, such as ABVD, seems to be very promising, as observed in the great success of Rituximab treatment (16).
|
Acknowledgments |
|---|
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.
We thank Dr. Toshitada Takahashi, president of Aichi Cancer Center Hospital and Research Institute, for his critical review of the manuscript; Kyowa Hakko Kogyo Incorporation (Tokyo) for providing us with anti-CCR4 mAb (KM2160) and chimeric anti-CCR4 mAb (KM2760) and for letting us view the data from the KM2760 study in cynomolgus monkeys; Seizo Nagaya and Chiori Fukuyama for their skillful technical assistance; and Takashi Sato for helpful advice and discussions.
|
Footnotes |
|---|
3 Unpublished data from Kyowa Hakko Kogyo Incorporation. 
Received 1/25/06. Revised 3/24/06. Accepted 3/30/06.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-induced, CD8+ T-cell-dependent immune defense of B16 melanoma. Cancer Res 2001;61:8643–6.This article has been cited by other articles:
|
|
 |
|
  A. Ito, T. Ishida, A. Utsunomiya, F. Sato, F. Mori, H. Yano, A. Inagaki, S. Suzuki, H. Takino, M. Ri, et al. Defucosylated Anti-CCR4 Monoclonal Antibody Exerts Potent ADCC against Primary ATLL Cells Mediated by Autologous Human Immune Cells in NOD/Shi-scid, IL-2R{gamma}null Mice In Vivo J. Immunol., October 1, 2009; 183(7): 4782 - 4791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Di Stasi, B. De Angelis, C. M. Rooney, L. Zhang, A. Mahendravada, A. E. Foster, H. E. Heslop, M. K. Brenner, G. Dotti, and B. Savoldo T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model Blood, June 18, 2009; 113(25): 6392 - 6402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schumacher, N. Brachwitz, S. Sohr, K. Engeland, S. Langwisch, M. Dolaptchieva, T. Alexander, A. Taran, S. F. Malfertheiner, S.-D. Costa, et al. Human Chorionic Gonadotropin Attracts Regulatory T Cells into the Fetal-Maternal Interface during Early Human Pregnancy J. Immunol., May 1, 2009; 182(9): 5488 - 5497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-J. Qin, H.-Z. Shi, J.-M. Deng, Q.-L. Liang, J. Jiang, and Z.-J. Ye CCL22 Recruits CD4-positive CD25-positive Regulatory T Cells into Malignant Pleural Effusion Clin. Cancer Res., April 1, 2009; 15(7): 2231 - 2237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Mailloux and M. R. I. Young NK-Dependent Increases in CCL22 Secretion Selectively Recruits Regulatory T Cells to the Tumor Microenvironment J. Immunol., March 1, 2009; 182(5): 2753 - 2765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gobert, I. Treilleux, N. Bendriss-Vermare, T. Bachelot, S. Goddard-Leon, V. Arfi, C. Biota, A. C. Doffin, I. Durand, D. Olive, et al. Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome Cancer Res., March 1, 2009; 69(5): 2000 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sanchez-Espiridion, A. Sanchez-Aguilera, C. Montalban, C. Martin, R. Martinez, J. Gonzalez-Carrero, C. Poderos, C. Bellas, M. F. Fresno, C. Morante, et al. A TaqMan Low-Density Array to Predict Outcome in Advanced Hodgkin's Lymphoma Using Paraffin-Embedded Samples Clin. Cancer Res., February 15, 2009; 15(4): 1367 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lamprecht, S. Kreher, I. Anagnostopoulos, K. Johrens, G. Monteleone, F. Jundt, H. Stein, M. Janz, B. Dorken, and S. Mathas Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3{alpha} Blood, October 15, 2008; 112(8): 3339 - 3347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. M. Patten, A. G. S. Buggins, J. Richards, A. Wotherspoon, J. Salisbury, G. J. Mufti, T. J. Hamblin, and S. Devereux CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment Blood, May 15, 2008; 111(10): 5173 - 5181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ma, L. Visser, H. Roelofsen, M. de Vries, A. Diepstra, G. van Imhoff, T. van der Wal, M. Luinge, G. Alvarez-Llamas, H. Vos, et al. Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes Blood, February 15, 2008; 111(4): 2339 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Deola, M. C. Panelli, D. Maric, S. Selleri, N. I. Dmitrieva, C. Y. Voss, H. Klein, D. Stroncek, E. Wang, and F. M. Marincola Helper B Cells Promote Cytotoxic T Cell Survival and Proliferation Independently of Antigen Presentation through CD27/CD70 Interactions J. Immunol., February 1, 2008; 180(3): 1362 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Haas, L. Schopp, B. Storch-Hagenlocher, B. Fritzsching, C. Jacobi, L. Milkova, B. Fritz, A. Schwarz, E. Suri-Payer, M. Hensel, et al. Specific recruitment of regulatory T cells into the CSF in lymphomatous and carcinomatous meningitis Blood, January 15, 2008; 111(2): 761 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yano, T. Ishida, A. Inagaki, T. Ishii, J. Ding, S. Kusumoto, H. Komatsu, S. Iida, H. Inagaki, and R. Ueda Defucosylated Anti CC Chemokine Receptor 4 Monoclonal Antibody Combined with Immunomodulatory Cytokines: A Novel Immunotherapy for Aggressive/Refractory Mycosis Fungoides and Sezary Syndrome Clin. Cancer Res., November 1, 2007; 13(21): 6494 - 6500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Z. Yang, A. J. Novak, S. C. Ziesmer, T. E. Witzig, and S. M. Ansell CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells Blood, October 1, 2007; 110(7): 2537 - 2544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tanijiri, T. Shimizu, K. Uehira, T. Yokoi, H. Amuro, H. Sugimoto, Y. Torii, K. Tajima, T. Ito, R. Amakawa, et al. Hodgkin's Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naive T cells J. Leukoc. Biol., September 1, 2007; 82(3): 576 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Juszczynski, J. Ouyang, S. Monti, S. J. Rodig, K. Takeyama, J. Abramson, W. Chen, J. L. Kutok, G. A. Rabinovich, and M. A. Shipp The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma PNAS, August 7, 2007; 104(32): 13134 - 13139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lee, S. G. Kang, and C. H. Kim FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues J. Immunol., January 1, 2007; 178(1): 301 - 311. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
