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Review

Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms

Gregory Lizée, Laszlo G. Radvanyi, Willem W. Overwijk and Patrick Hwu
DOI: 10.1158/1078-0432.CCR-06-0944 Published August 2006

Abstract

Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4+CD25+ T-regulatory cells, type 1 regulatory T cells, natural killer T cells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.

  • cancer
  • regulatory cells
  • Treg cells
  • Tr1 cells
  • natural killer T cells
  • immature myeloid cells

The initial wave of enthusiasm experienced by many cancer immunologists with the identification of tumor-associated antigens recognized by immune cells has since given way to a more tempered optimism, based largely on the low response rates using a number of different immunotherapeutic approaches. Several formulations of cancer vaccines designed to induce tumor-specific T cell responses have now been extensively tested in patients with cancer at multiple centers, including immunization with tumor antigen-encoding naked DNA, viral vectors, antigenic peptides, peptide or tumor lysate–pulsed autologous dendritic cells (DC), gene-modified autologous tumor cell vaccines, and tumor-derived heat shock protein preparations (1–7). Although many of these vaccination approaches elicit significant numbers of tumor antigen–specific T cells in the blood of cancer patients, objective clinical regressions remain rare (8–10).

This paradoxical observation of tumor growth in the face of large numbers of activated, circulating tumor-reactive T cells suggests that their antitumor efficacy is actively attenuated in vivo. Evidence for this idea has been accumulating rapidly during the past decade, fueled by the discovery of a number of different immunoregulatory cell types, soluble factors, and mechanisms that limit the strength and duration of immune responses. Such multiple, redundant regulatory mechanisms have probably evolved to induce tolerance to self and seem to be essential for the normal control of autoimmunity. Several of these have now also been strongly implicated as significant barriers to the generation of effective antitumor immune responses.

In light of this recent evidence, it would now seem that the most promising and synergistic approaches for cancer immunotherapy will be ones designed to augment specific antitumor immunity while simultaneously reducing the effect of immunoregulatory mechanisms in vivo. Tumor immunologists have made considerable clinical progress in recent years with the first part of this equation. Following the identification of numerous tumor-associated antigens expressed by different tumor cell types, the induction of tumor antigen–reactive T cells with specific vaccination approaches and expansion of tumor-specific T cells to large numbers for adoptive transfer into patients have now become feasible. Nonetheless, we are just now beginning to clinically consider the latter challenge of preexisting regulatory cells and mechanisms in vivo that present an impediment to the effectiveness of our existing immunotherapies.

In this review, we discuss four major subtypes of immunoregulatory cells (Table 1 ) and briefly outline the evidence describing their role in impairing antitumor immune responses. One current strategy for eliminating these cells in vivo is through chemotherapeutic lymphoablation, and we review the existing evidence that lymphodepletion of patients with cancer before adoptive T cell transfer substantially increases the antitumor efficacy of the transferred cells. However, this approach can induce a significant degree of collateral damage to the patients' beneficial immune cells through the elimination of endogenous antiviral and memory cells. With this in mind, we describe newer strategies designed to more selectively target specific immunoregulatory cell types or specifically block immunosuppressive molecules expressed by regulatory, effector, tumor, or tumor stromal cells in vivo.

View this table:
Table 1.

Immune cells implicated in the suppression of antitumor immunity

CD4+CD25+ T-Regulatory Cells

The best characterized of the immunoregulatory cells are CD4+CD25+ natural T-regulatory (Treg) cells. They represent a functionally distinct lineage of T cells crucial for the maintenance of peripheral tolerance in vivo. A major distinction from other regulatory cell types is that Treg cells differentiate under normal conditions in the thymus into a mature regulatory subset, as opposed to being induced in the periphery from naïve CD4+ T cells (11). Treg cells represent approximately 5% to 10% of peripheral CD4+ cells and constitutively express CD25 (IL-2Rα), glucocorticoid-induced tumor necrosis factor receptor (GITR), CTL antigen 4 (CTLA-4), and the transcription factor Foxp3 (12–15). The exact mechanism of action of Treg cells is still under debate, as is the nature of their antigen recognition. Recent studies suggest that Treg cells can recognize self-antigens, including tumor-associated antigens with high avidity and, when stimulated, suppress autoimmunity, tumor immunity, and graft rejection (11, 16, 17).

In mice, absence or depletion of Treg cells leads to the autoimmune destruction of a variety of tissues (18, 19). In addition, Treg cell inhibition or depletion before tumor challenge has been shown to induce effective immune responses against multiple syngeneic tumors in a number of different mouse strains (20–22). This enhanced antitumor immunity is primarily mediated by CD8+ T cells, but there is some evidence that CD4+ and natural killer (NK) cells may also be involved. Anti-CD25 treatment also enhances the efficacy of tumor vaccines, inducing a stronger long-term memory response (22). Importantly, removal of Treg cells has been shown to elicit effective antitumor immunity against established murine tumors (23, 24). In an adoptive immunotherapy model of melanoma, transfer of CD4+CD25+ Treg cells, but not CD4+CD25− T cells, effectively prevented CD8+ T cell–mediated tumor destruction (25).

Recent studies of Treg cells in human cancer have shown elevated Treg levels in the peripheral blood and/or tumor microenvironment of patients with melanoma, Hodgkin lymphoma, and non–small cell lung, ovarian, gastrointestinal, pancreatic, and breast cancer (26–31). In a large-scale study of 104 patients with ovarian carcinoma, CD4+CD25+Foxp3+ cells were shown to accumulate in tumors, in which they suppressed tumor-specific T cell immunity (32). Most notably, the number of Treg cells present within tumor biopsy specimens of different patients was highly inversely correlated with patient survival (32).

The mechanism by which Treg cells suppress the activation, proliferation, and cytokine production of antigen-specific helper CD4+ and killer CD8+ T cells is poorly understood, but it is known to require the activation of Treg cells through their T cell receptor and direct contact of the Treg cell with the responding T cell (Fig. 1A ; ref. 33). Antibody blocking studies have shown no clear role for the candidate surface molecules GITR or CTLA-4 in directly mediating suppression (34–36). Although CD4+CD25+ Treg cells can produce the immunosuppressive cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β) on activation, they do not seem to be important for inducing target cell suppression (37–39). The lack of cell type–specific markers with which to identify and isolate Treg cells has hampered efforts to better understand their mechanism of action and allow for the design of reagents that could specifically target these cells in vivo.

Fig. 1.
Fig. 1.

The four major subtypes of immunoregulatory cells and their proposed mechanisms of action. (A) CD4+CD25+ Treg cells, (B) Type 1 regulatory T cells, (C) invariant natural killer T cells, and (D) immature myeloid cells. Please refer to the text for details.

Type 1 Regulatory T Cells

Type 1 regulatory T (Tr1) cells comprise a subset of CD4+ T cells that are induced by antigen-specific activation in the presence of IL-10 (40). Such Tr1 cells can induce T cell anergy and suppression of immune responses, primarily via the production of high levels of cytokines IL-10 and TGF-β (41). Human Tr1 cells have been shown to mediate tolerance to kidney or liver allografts, and their presence was also correlated with long-term acceptance of hematopoietic stem cell grafts (42, 43). In general, their physiologic role seems to be the down-regulation of immune responses against self-antigens and pathogens and the induction of tolerance to environmental allergens (44–50).

Although studies on Tr1 cells and cancer have only just begun, Tr1 cells have been reported to be associated with cancer in both humans and in animal models (27, 51). A wide variety of tumor cell types are known to secrete IL-10 directly or induce its secretion by other cells, and increased serum levels of IL-10 have been reported in cancer patients (52–61). Long-term T cell receptor stimulation of tumor antigen–specific CD4+ T cells in the presence of IL-10 could therefore provide conditions that would favor the induction of Tr1 cells in the tumor microenvironment. Interestingly, Tr1-like CD4+ T cells, isolated either from the blood of melanoma patients or induced by repeated in vitro stimulation with tumor cells, have been shown to secrete IL-10 in response to the recognition of MHC class II restricted tumor antigens expressed on melanoma cells (62, 63).

The two major effector cytokines produced by Tr1 cells, IL-10 and TGF-β, are potent immunoregulatory cytokines with complex effects on multiple cell types (Fig. 1B). IL-10 can suppress T cell responses indirectly through the inhibition of MHC and costimulatory molecule expression and cytokine production by antigen-presenting cells, including DCs, Langerhans cells, and macrophages (55, 64–67). IL-10 can also directly regulate T cells by inhibiting their ability to proliferate and produce cytokines, including IL-2 and tumor necrosis factor-α (TNF-α), and has also been implicated in activation-induced cell death of T cells (55, 68–72). TGF-β inhibits T cell proliferation, cytokine production, and cytotoxicity, and can act at all stages of T cell differentiation (73, 74). Under some conditions, TGF-β can also inhibit antigen-presenting cell function by suppressing maturation and IFN-γ production and inducing MHC class II down-regulation (75–77). TGF-β-secreting CD4+ regulatory cells are alternatively referred to as TH3 cells. The broadly immunosuppressive role of cytokines produced by Tr1 cells suggests that these cells could play a significant role in shaping the tumor microenvironment to favor the growth of tumor cells.

Invariant Natural Killer T Cells

A third subset of immunoregulatory T cells express the NK cell marker, NK1.1, and recognize glycolipid antigens presented by the MHC class Ib molecule CD1d through a highly restricted T cell receptor repertoire (78, 79). Invariant NKT (iNKT) cells from both humans (expressing the Vα24 T cell receptor chain) and mice (expressing the Vα14 chain) are strongly activated by the marine sponge–derived glycolipid, α-galactosylceramide (α-GalCer), leading to the rapid secretion of both T helper 1 and 2 (TH1 and TH2) cytokines (80–83). Paradoxically, iNKT cells have been implicated in both the augmentation and suppression of antitumor responses (79, 84).

IFN-γ, which is rapidly produced by iNKT cells on activation with α-GalCer, triggers prolonged IFN-γ production by NK cells, which can subsequently inhibit tumor growth by blocking angiogenesis and inducing NK tumor cell killing via a tumor necrosis factor–related apoptosis inducing ligand (TRAIL)–dependent mechanism (85–87). iNKT activation also influences adaptive antitumor immune responses by increasing DC maturation, cross-presentation, and T cell priming against tumor antigens (88–90). Early clinical trials studying direct α-GalCer injection or infusion of α-GalCer-loaded DCs into patients with solid tumors reported no dose-related toxic effects, and although significant and sustained increases in iNKT cell numbers have been observed, no patients showed objective responses to this treatment (91–93). The recent identification of endogenous mammalian glycolipid ligands presented by CD1d has raised the possibility that iNKT cells may secrete proinflammatory cytokines in response to the recognition of pathogen-derived glycolipids, or altered glycolipid antigens generated in cells by pathogen-induced stress, or by defective glycosylation mechanisms, which have been frequently reported in cancer cells (94–96).

In contrast to their documented antitumor effects, iNKT cells have also been reported in a number of mouse models to suppress antitumor immune responses (97–99). This suppression seems to be mediated at least in part by secretion of TH2 cytokines IL-4 and IL-13 by iNKT cells in response to tumor-derived factors (Fig. 1C; ref. 98). There is evidence that the IL-13 produced by iNKT cells induces myeloid dendritic cells to produce TGF-β which, in turn, directly suppresses CD8+ CTLs (100).

Patients with cancer frequently show reduced levels of peripheral blood iNKT cells compared with healthy donors and, in addition to a diminished ability to proliferate in response to α-GalCer, they produce little IFN-γ while still maintaining functional IL-4 production (91, 101–105). The cytokine polarization by iNKT cells, in which TH1 cytokines are deficient and immune responses are skewed toward the production of TH2 cytokines, seems to be consistent in both mouse models and cancer patients (83). This defect seems to be reversible in vitro by stimulation with α-GalCer-loaded DCs, suggesting a possible therapeutic means to relieve iNKT-induced immune suppression in patients with cancer (105).

Immature Myeloid Cells and Immature Dendritic Cells

There is accumulating evidence from mouse models and cancer patients that progressive tumor growth is associated with an increased frequency of immature myeloid cells (iMC) and immature DCs (iDC) that can inhibit tumor-specific T lymphocytes (106–108). iMCs and iDCs can be induced by tumor-derived soluble factors, including vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor, IL-6, granulocyte-macrophage colony-stimulating factor, IL-10, and gangliosides (108). These factors inhibit the differentiation of myeloid cells in vivo, leading to decreased levels of functionally competent, mature antigen-presenting cells, accumulation of iDCs that are unable to up-regulate MHC class II and costimulatory molecules or produce appropriate cytokines, and increased production of iMCs (109–112). The proangiogenic cytokine VEGF seems to be a major mediator of this disrupted DC differentiation, and tumors can secrete copious amounts of VEGF detectable in the serum of patients with cancer (113–115). In vitro studies have shown that these VEGF levels block DC maturation, leading to the appearance of iMCs, whereas blocking VEGF augments normal DC differentiation and function (116).

Tumors from patients with cancer often contain iDCs with reduced allostimulatory capacity (117, 118). Furthermore, such tumor-derived iDCs often express low levels of the costimulatory molecules CD80 and CD86 and often fail to up-regulate them even in the presence of the DC maturation factors TNF-α or CD40 ligand (119, 120). Increased circulating levels of such iDCs have also been observed in the peripheral blood of patients with lung, breast, head and neck, and esophageal cancer (108, 110, 111). The failure of iDCs to provide adequate costimulation during T cell priming, together with their inability to secrete IL-12, can lead to T cell anergy, and in some cases, activation-induced cell death (108, 119, 121, 122). Importantly, patients with cancer often show a significant reduction in circulating levels of mature DCs that can be reversed on surgical removal of tumors, an observation that has also been reported in several mouse models (109, 111, 112, 123–125). Thus, abnormal differentiation and maturation of DCs in vivo, mediated by tumor-derived soluble factors, likely plays a substantial role in preventing the effective priming of a productive, T cell–mediated antitumor immune response.

iMCs are a heterogeneous population that include immature cells of the granulocyte and monocyte/macrophage lineage (108). These cells have been shown to accumulate in the peripheral blood of patients with breast, lung, or head and neck cancer, and this accumulation is often associated with a decrease in DC numbers (112). Similar to iDCs, circulating levels of iMCs have been well correlated with stage of disease and poorer prognosis, and surgical resection of tumors has been shown to decrease the number of peripheral blood iMCs in both human and animal models (126–128).

iMCs mediate their immunosuppressive activity through the inhibition of IFN-γ production by CD8+ T cells in response to MHC class I–associated peptide epitopes presented on the iMC surface (129). This effect requires direct cell-to-cell contact and is mediated by reactive oxygen and nitrogen species, such as hydrogen peroxide (H2O2) and nitric oxide (NO), secreted by the iMCs in close proximity to the T cell (Fig. 1D; refs. 130, 131). Although the precise mechanism of action on T cells has yet to be fully elucidated, there is some indication that iMCs act, in part, through down-regulation of the CD3ζ chain on responding CD8+ T cells (130, 132). Recently, a population of iMCs has been described in the peripheral blood of cancer patients having high arginase-1 activity capable of depleting local arginine levels and down-modulating CD3ζ levels on T cells. Depletion of this iMC subset in vitro restored CD3ζ expression and normal T cell responses (133, 134). Although freshly isolated iMCs do not seem to be capable of suppressing CD4+ T cells, cultured iMCs have been shown to induce CD4+ T cell apoptosis through the production of arginase and NO (135).

In summary, there is much evidence to suggest that the balance of immature and mature myeloid cells in vivo can have a significant effect on both naturally occurring and vaccine-induced antitumor T cell responses. It is becoming increasingly apparent that effective cancer immunotherapy may require the correction of aberrant myeloid cell differentiation frequently observed in tumor-bearing hosts.

Elimination of Regulatory Cells by Lymphodepletion

The development of clinical reagents designed to eliminate relevant subsets of immunoregulatory cells in vivo remains an important goal for cancer immunotherapy. Currently, the best strategy for eliminating regulatory cells in patients with cancer involves lymphoablative conditioning, which has been best studied in the context of adoptive T cell transfer studies in patients with melanoma. Evidence from both animal studies and human clinical trials suggests that the host immune environment can significantly affect the efficacy of adoptive T cell transfer therapy (136). Mouse tumor models have shown that sublethal, lymphodepleting doses of irradiation before adoptive transfer of tumor antigen–specific lymphocytes substantially increases the persistence and antitumor activity of the transferred cells (137, 138). In addition, preconditioning mice with low doses of chemotherapeutic agents, such as cyclophosphamide and 5-fluorouracil, prior to antitumor vaccination has been found to markedly augment antigen-specific T cell responses and tumor control (139–143).

Parallel findings in humans have shown that the addition of a lymphodepleting conditioning regimen prior to adoptive T cell transfer therapy for patients with metastatic melanoma significantly improves clinical response rates (144, 145). Stage IV melanoma patients enrolled in a recent clinical trial received a lymphodepleting chemotherapy regimen that consisted of cyclophosphamide and 5-fluorouracil before administration of highly selected, expanded, tumor-reactive tumor-infiltrating lymphocyte cultures, and IL-2 therapy (146). The lymphodepletion regimen resulted in a transient myelosuppression and the elimination of all endogenous circulating lymphocytes for ∼1 week, after which time, patients recovered endogenous marrow function and reconstituted their lymphocyte compartments toward normal levels within 3 to 4 weeks (144, 147).

Eighteen (51%) of 35 patients treated in this trial experienced objective clinical responses, including 3 ongoing complete responses and 15 partial responses with a mean duration of 11.5 months. Significant levels of tumor regression were observed in metastatic deposits in the liver, lungs, brain, cutaneous and subcutaneous tissues, and lymph nodes (146, 148). Interestingly, a number of responding patients showed marked evidence of lymphoproliferation of the transferred cells, and clinical responses were highly correlated with their in vivo persistence (146, 149–151). These results underscore the significant potential that lymphodepleting regimens, which eliminate circulating regulatory cells, have to enhance the efficacy of adoptive T cell transfer immunotherapy in patients with cancer. It will be critical to determine the relationship between T cell persistence, lymphoproliferation, and the role of any re-emerging regulatory T cell subsets in long-term tumor control and what the differences are between responding and nonresponding patients in this regard.

Future Approaches to Circumventing Immunoregulation

Lymphoablative chemotherapy, although currently beneficial for patients with cancer in adoptive transfer settings, is clearly a “sledgehammer” approach to eliminating immunoregulatory cells that may abrogate the efficacy of immunotherapy. In addition, these regimens are fairly toxic and lead to increased susceptibility to viral and/or bacterial infection. An important future goal for cancer immunologists is to develop more refined methods of eliminating specific immunoregulatory cells that will not result in collateral damage to patients' beneficial immune cells. Increasing our knowledge of the precise mechanisms of antitumor immunoregulation will inevitably lead to the development of more specific and effective clinical reagents capable of interfering with suppression at the molecular level.

CD4+CD25+ Treg cells are currently the only regulatory cell subtype that has been specifically targeted for elimination in human studies. Two approved compounds, human anti-Tac (anti-CD25) and ONTAK (IL-2 receptor-binding domain of IL-2 fused to diphtheria toxin), have been used in clinical trials for the treatment of cancer with, thus far, limited success (152, 153). Although trials are still proceeding, a major concern is the specificity of this approach. CD25 is also expressed on activated CD4+ helper T cells and activated CD8+ cytotoxic T cells, in which it helps drive the expansion and survival of effector cells (154). Thus, elimination of the CD25+ cell subsets may prove more detrimental than helpful. Preclinical mouse models on which these trials are based have eliminated Treg cells before activation of relevant tumor-reactive T cell subsets (20, 22). By contrast, in patients with cancer, tumor-specific T cells are often activated before therapeutic intervention, suggesting that the two systems may not be comparable.

The systemic depletion of any of the regulatory cell subsets presents at least two important caveats: (a) none of the regulatory cell subsets express currently known unique markers that can be targeted without affecting nonregulatory cells, and (b) removal of an entire population of regulatory cells in vivo could potentially result in the induction of autoimmunity. With these considerations in mind, strategies designed to target subsets of regulatory cells present within the local tumor microenvironment or tumor draining lymph nodes may be warranted. Although the means to accomplish this are not currently available, this type of approach may, in some cases, be enough to tip the immunologic balance to favor antitumor immunity, with minimal adverse effects.

A promising alternative strategy for alleviating antitumor immunoregulation in vivo involves the specific blocking of molecules that can mediate immune suppression. The list of potentially targetable molecules is rapidly growing, and these can be expressed either on the cell surface or secreted by tumor cells, tumor stroma, regulatory cells, or effector cells (Table 2 ). One of the best-studied blocking reagents targets CTLA-4, a transmembrane protein expressed by both CD4+CD25+ Treg cells and effector T cells. CTLA-4 is up-regulated on conventional T cells on antigen stimulation and functions as a coinhibitory receptor to attenuate activation during T cell priming and limiting effector cell expansion (155). The constitutively high CTLA-4 expression on Treg cells has been shown to induce DCs to turn on tryptophan catabolism via indoleamine 2,3-dioxygenase, causing local depletion of this essential amino acid and effectively crippling T cell priming and proliferation (156, 157).

View this table:
Table 2.

Potentially targetable immunoregulatory molecules

Based on successful preclinical murine tumor therapy models (158, 159), a number of ongoing and completed clinical trials have used anti-CTLA-4 to treat patients with cancer of different histologic types. The initial reports have been encouraging, with two groups documenting significant increases in antitumor immunity in vaccinated melanoma patients following anti-CTLA-4 treatment, including the induction of some objective tumor regressions (160–162). However, this treatment has also been associated with inducing a wide variety of grade 3 and 4 autoimmune manifestations, potentially limiting its usefulness as a clinical reagent (161, 162).

Another promising molecular target is the immunoinhibitory receptor programmed death 1 (PD-1), which is expressed by both helper CD4+ and cytotoxic CD8+ T cells. The ligand for PD-1, the B7 family member B7-H1, is expressed on a wide variety of human cancer cells, including lung, ovarian, colon, and melanoma (163). Ligation of PD-1 on T cells by B7-H1 has been shown to decrease proliferation and cytokine secretion and induce apoptosis of human T cells (164, 165). Furthermore, antibody blockade of PD-1 and/or B7-H1 has been shown to significantly augment immunotherapy in mouse tumor models, suggesting that clinical trials using this approach may be warranted (166–168).

Targeting of soluble immunoregulatory molecules could also prove useful for enhancing the immunotherapy of cancer. Neutralization of immunosuppressive cytokines IL-10, IL-13, TGF-β, and VEGF through the administration of specific monoclonal antibodies or soluble receptors may prove synergistic with other cancer vaccine or adoptive transfer strategies by reducing anti-inflammatory signals that limit antitumor immunity and inhibit DC differentiation. One recent addition to anticancer armamentarium is bevacizumab, a humanized monoclonal antibody against VEGF that is proving effective in metastatic colon cancer, and more recently in metastatic breast cancer, as an antiangiogenic agent (169–172). Although bevacizumab is proposed to act by blocking tumor angiogenesis (which has not been proven directly in humans yet), it may also inhibit the immune suppressive effects of VEGF on DC differentiation and iMC production. Indoleamine 2,3-dioxygenase, an enzyme produced by macrophages, DCs, and many human tumor cells, inhibits T cell proliferation by catabolizing and depleting local tryptophan, and thus, might represent another attractive molecular target (173, 174). Immune suppression may also be circumvented by targeting two enzymes expressed by myeloid suppressor and some tumor cells, inducible NO synthase 2 and arginase-1 (175, 176). These metabolic enzymes act to generate NO and deplete local arginine, respectively, and can act synergistically in the tumor microenvironment to induce the apoptosis of activated T cells and enhance tumor growth (177–182).

Conclusions

Two decades after the pioneering studies by North and colleagues demonstrating induction of suppressor cells in murine sarcoma models (183–186), there now exists overwhelming evidence from both human and animal studies that regulatory immune cells play an active and significant role in the progression of cancer. Thus, there is a clear rationale for developing clinical strategies to diminish these regulatory influences, with the ultimate goal of augmenting antitumor immunity. It should be mentioned that although this review has focused on four of the most well characterized regulatory cell types, other subsets have also been reported (including CD8+ regulatory cells, CD4+ cells that show features of both natural and adaptive Treg, and γδ T cells), further underscoring the heterogeneous nature of immunoregulation.

Future challenges include the identification of unique regulatory cell markers that can be used to more specifically target these cells in vivo and a more accurate characterization of the molecular nature of immune suppression. The ability to diagnose which regulatory mechanisms are dominant within the tumor microenvironment of individual patients and when they are initiated during cancer progression will also be of paramount importance for implementation of effective immunotherapy. Meeting these challenges should lead to substantially increased specificity of immune interventions, thus allowing for harnessing of the benefits of enhanced antitumor immunity, while avoiding the simultaneous induction of unwanted autoimmunity.

Acknowledgments

The authors would like to thank Linda Duggan for providing graphical assistance on Figure 1.

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.

    • Accepted May 31, 2006.
    • Received April 17, 2006.

References

  1. ↵
    Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998;4:321–7.
    OpenUrlCrossRefPubMed
  2. Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998;4:328–32.
    OpenUrlCrossRefPubMed
  3. Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK. Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 2000;88:232–8.
    OpenUrlCrossRefPubMed
  4. Chang AE, Redman BG, Whitfield JR, et al. A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer. Clin Cancer Res 2002;8:1021–32.
    OpenUrlAbstract/FREE Full Text
  5. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res 2003;9:2973–80.
    OpenUrlAbstract/FREE Full Text
  6. Soiffer R, Hodi FS, Haluska F, et al. Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol 2003;21:3343–50.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Stevenson FK, Ottensmeier CH, Johnson P, et al. DNA vaccines to attack cancer. Proc Natl Acad Sci U S A 2004;101:14646–52.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Jager E, Jager D, Knuth A. Antigen-specific immunotherapy and cancer vaccines. Int J Cancer 2003;106:817–20.
    OpenUrlCrossRefPubMed
  9. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–15.
    OpenUrlCrossRefPubMed
  10. ↵
    Mocellin S, Mandruzzato S, Bronte V, Lise M, Nitti D. Part I: vaccines for solid tumours. Lancet Oncol 2004;5:681–9.
    OpenUrlCrossRefPubMed
  11. ↵
    Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005;6:345–52.
    OpenUrlCrossRefPubMed
  12. ↵
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64.
    OpenUrlAbstract/FREE Full Text
  13. McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16:311–23.
    OpenUrlCrossRefPubMed
  14. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000;192:295–302.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–61.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Wang HY, Lee DA, Peng G, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 2004;20:107–18.
    OpenUrlCrossRefPubMed
  17. ↵
    Kronenberg M, Rudensky A. Regulation of immunity by self-reactive T cells. Nature 2005;435:598–604.
    OpenUrlCrossRefPubMed
  18. ↵
    Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184:387–96.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    McHugh RS, Shevach EM. Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 2002;168:5979–83.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    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 1999;163:5211–8.
    OpenUrlAbstract/FREE Full Text
  21. 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 1999;59:3128–33.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    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 2002;32:3267–75.
    OpenUrlCrossRefPubMed
  23. ↵
    Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. 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 2001;194:823–32.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Jones E, Dahm-Vicker M, Simon AK, et al. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:1.
    OpenUrlPubMed
  25. ↵
    Antony PA, Piccirillo CA, Akpinarli A, et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 2005;174:2591–601.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Javia LR, Rosenberg SA. CD4+CD25+ suppressor lymphocytes in the circulation of patients immunized against melanoma antigens. J Immunother 2003;26:85–93.
  27. ↵
    Marshall NA, Christie LE, Munro LR, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004;103:1755–62.
    OpenUrlAbstract/FREE Full Text
  28. Woo EY, Chu CS, Goletz TJ, 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 2001;61:4766–72.
    OpenUrlAbstract/FREE Full Text
  29. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A. CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 2003;98:1089–99.
    OpenUrlCrossRefPubMed
  30. Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002;169:2756–61.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    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 2003;9:606–12.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942–9.
    OpenUrlCrossRefPubMed
  33. ↵
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004;199:971–9.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135–42.
    OpenUrlCrossRefPubMed
  35. 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 2001;193:1285–94.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25 high regulatory cells in human peripheral blood. J Immunol 2001;167:1245–53.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295–302.
    OpenUrlAbstract/FREE Full Text
  38. Shevach EM, McHugh RS, Piccirillo CA, Thornton AM. Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 2001;182:58–67.
    OpenUrlCrossRefPubMed
  39. ↵
    Piccirillo CA, Letterio JJ, Thornton AM, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J Exp Med 2002;196:237–46.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev 2001;182:68–79.
    OpenUrlCrossRefPubMed
  41. ↵
    Levings MK, Bacchetta R, Schulz U, Roncarolo MG. The role of IL-10 and TGF-β in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol 2002;129:263–76.
    OpenUrlCrossRefPubMed
  42. ↵
    Bacchetta R, Bigler M, Touraine JL, et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994;179:493–502.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    VanBuskirk AM, Burlingham WJ, Jankowska-Gan E, et al. Human allograft acceptance is associated with immune regulation. J Clin Invest 2000;106:145–55.
    OpenUrlCrossRefPubMed
  44. ↵
    Kitani A, Chua K, Nakamura K, Strober W. Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J Immunol 2000;165:691–702.
    OpenUrlAbstract/FREE Full Text
  45. Yudoh K, Matsuno H, Nakazawa F, Yonezawa T, Kimura T. Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis. Arthritis Rheum 2000;43:617–27.
    OpenUrlCrossRefPubMed
  46. Khoo UY, Proctor IE, Macpherson AJ. CD4+ T cell down-regulation in human intestinal mucosa: evidence for intestinal tolerance to luminal bacterial antigens. J Immunol 1997;158:3626–34.
    OpenUrlAbstract
  47. Boussiotis VA, Tsai EY, Yunis EJ, et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest 2000;105:1317–25.
    OpenUrlCrossRefPubMed
  48. Plebanski M, Flanagan KL, Lee EA, et al. Interleukin 10-mediated immunosuppression by a variant CD4 T cell epitope of Plasmodium falciparum. Immunity 1999;10:651–60.
    OpenUrlCrossRefPubMed
  49. Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest 1998;102:98–106.
    OpenUrlCrossRefPubMed
  50. ↵
    Cavani A, Nasorri F, Prezzi C, Sebastiani S, Albanesi C, Girolomoni G. Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol 2000;114:295–302.
    OpenUrlCrossRefPubMed
  51. ↵
    Seo N, Hayakawa S, Takigawa M, Tokura Y. Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology 2001;103:449–57.
    OpenUrlCrossRefPubMed
  52. ↵
    Benjamin D, Knobloch TJ, Dayton MA. Human B-cell interleukin-10: B-cell lines derived from patients with acquired immunodeficiency syndrome and Burkitt's lymphoma constitutively secrete large quantities of interleukin-10. Blood 1992;80:1289–98.
    OpenUrlAbstract/FREE Full Text
  53. Gastl GA, Abrams JS, Nanus DM, et al. Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression. Int J Cancer 1993;55:96–101.
    OpenUrlCrossRefPubMed
  54. Dummer W, Bastian BC, Ernst N, Schanzle C, Schwaaf A, Brocker EB. Interleukin-10 production in malignant melanoma: preferential detection of IL-10-secreting tumor cells in metastatic lesions. Int J Cancer 1996;66:607–10.
    OpenUrlCrossRefPubMed
  55. ↵
    Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765.
    OpenUrlCrossRefPubMed
  56. Fiore F, Nuschak B, Peola S, et al. Exposure to myeloma cell lysates affects the immune competence of dendritic cells and favors the induction of Tr1-like regulatory T cells. Eur J Immunol 2005;35:1155–63.
    OpenUrlCrossRefPubMed
  57. Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS. Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 2004;173:4352–9.
    OpenUrlAbstract/FREE Full Text
  58. Beckebaum S, Zhang X, Chen X, et al. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res 2004;10:7260–9.
    OpenUrlAbstract/FREE Full Text
  59. Ebrahimi B, Tucker SL, Li D, Abbruzzese JL, Kurzrock R. Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer 2004;101:2727–36.
    OpenUrlCrossRefPubMed
  60. Gotlieb WH, Abrams JS, Watson JM, Velu TJ, Berek JS, Martinez-Maza O. Presence of interleukin 10 (IL-10) in the ascites of patients with ovarian and other intra-abdominal cancers. Cytokine 1992;4:385–90.
    OpenUrlCrossRefPubMed
  61. ↵
    Mori N, Gill PS, Mougdil T, Murakami S, Eto S, Prager D. Interleukin-10 gene expression in adult T-cell leukemia. Blood 1996;88:1035–45.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    Brady MS, Eckels DD, Lee F, Ree SY, Lee JS. Cytokine production by CD4+ T-cells responding to antigen presentation by melanoma cells. Melanoma Res 1999;9:173–80.
    OpenUrlPubMed
  63. ↵
    Chakraborty NG, Li L, Sporn JR, Kurtzman SH, Ergin MT, Mukherji B. Emergence of regulatory CD4+ T cell response to repetitive stimulation with antigen-presenting cells in vitro: implications in designing antigen-presenting cell-based tumor vaccines. J Immunol 1999;162:5576–83.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    Ding L, Shevach EM. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol 1992;148:3133–9.
    OpenUrlAbstract
  65. Kawamura T, Furue M. Comparative analysis of B7-1 and B7-2 expression in Langerhans cells: differential regulation by T helper type 1 and T helper type 2 cytokines. Eur J Immunol 1995;25:1913–7.
    OpenUrlCrossRefPubMed
  66. Koch F, Stanzl U, Jennewein P, et al. High level IL-12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J Exp Med 1996;184:741–6.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Redpath S, Angulo A, Gascoigne NR, Ghazal P. Murine cytomegalovirus infection down-regulates MHC class II expression on macrophages by induction of IL-10. J Immunol 1999;162:6701–7.
    OpenUrlAbstract/FREE Full Text
  68. ↵
    de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993;150:4754–65.
    OpenUrlAbstract/FREE Full Text
  69. Taga K, Mostowski H, Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood 1993;81:2964–71.
    OpenUrlAbstract/FREE Full Text
  70. Bejarano MT, de Waal Malefyt R, Abrams JS, et al. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. Int Immunol 1992;4:1389–97.
    OpenUrlAbstract/FREE Full Text
  71. Georgescu L, Vakkalanka RK, Elkon KB, Crow MK. Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. J Clin Invest 1997;100:2622–33.
    OpenUrlCrossRefPubMed
  72. ↵
    Ayala A, Chung CS, Song GY, Chaudry IH. IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis. Cytokine 2001;14:37–48.
    OpenUrlCrossRefPubMed
  73. ↵
    Letterio JJ, Roberts AB. Regulation of immune responses by TGF-β. Annu Rev Immunol 1998;16:137–61.
    OpenUrlCrossRefPubMed
  74. ↵
    Gorelik L, Flavell RA. Transforming growth factor-β in T-cell biology. Nat Rev Immunol 2002;2:46–53.
    OpenUrlCrossRefPubMed
  75. ↵
    Bogdan C, Nathan C. Modulation of macrophage function by transforming growth factor β, interleukin-4, and interleukin-10. Ann N Y Acad Sci 1993;685:713–39.
    OpenUrlCrossRefPubMed
  76. Borkowski TA, Letterio JJ, Farr AG, Udey MC. A role for endogenous transforming growth factor β1 in Langerhans cell biology: the skin of transforming growth factor β1 null mice is devoid of epidermal Langerhans cells. J Exp Med 1996;184:2417–22.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    Geissmann F, Revy P, Regnault A, et al. TGF-β1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 1999;162:4567–75.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    Fowlkes BJ, Kruisbeek AM, Ton-That H, et al. A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vβ gene family. Nature 1987;329:251–4.
    OpenUrlCrossRefPubMed
  79. ↵
    Wilson SB, Delovitch TL. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 2003;3:211–22.
    OpenUrlCrossRefPubMed
  80. ↵
    Koseki H, Asano H, Inaba T, et al. Dominant expression of a distinctive V14+ T-cell antigen receptor α chain in mice. Proc Natl Acad Sci U S A 1991;88:7518–22.
    OpenUrlAbstract/FREE Full Text
  81. Dellabona P, Padovan E, Casorati G, Brockhaus M, Lanzavecchia A. An invariant Vα24-JαQ/Vβ11 T cell receptor is expressed in all individuals by clonally expanded CD4−8− T cells. J Exp Med 1994;180:1171–6.
    OpenUrlAbstract/FREE Full Text
  82. Kawano T, Cui J, Koezuka Y, et al. CD1d-restricted and TCR-mediated activation of vα14 NKT cells by glycosylceramides. Science 1997;278:1626–9.
    OpenUrlAbstract/FREE Full Text
  83. ↵
    van der Vliet HJ, Molling JW, von Blomberg BM, et al. The immunoregulatory role of CD1d-restricted natural killer T cells in disease. Clin Immunol 2004;112:8–23.
    OpenUrlCrossRefPubMed
  84. ↵
    Smyth MJ, Godfrey DI. NKT cells and tumor immunity: a double-edged sword. Nat Immunol 2000;1:459–60.
    OpenUrlCrossRefPubMed
  85. ↵
    Smyth MJ, Crowe NY, Pellicci DG, et al. Sequential production of interferon-γ by NK1.1(+) T cells and natural killer cells is essential for the antimetastatic effect of α-galactosylceramide. Blood 2002;99:1259–66.
    OpenUrlAbstract/FREE Full Text
  86. Hayakawa Y, Takeda K, Yagita H, et al. IFN-γ-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, α-galactosylceramide. Blood 2002;100:1728–33.
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Smyth MJ, Cretney E, Takeda K, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon γ-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001;193:661–70.
    OpenUrlAbstract/FREE Full Text
  88. ↵
    Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman RM. Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med 2003;198:267–79.
    OpenUrlAbstract/FREE Full Text
  89. Stober D, Jomantaite I, Schirmbeck R, Reimann J. NKT cells provide help for dendritic cell-dependent priming of MHC class I-restricted CD8+ T cells in vivo. J Immunol 2003;170:2540–8.
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Munz C, Steinman RM, Fujii S. Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J Exp Med 2005;202:203–7.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Giaccone G, Punt CJ, Ando Y, et al. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 2002;8:3702–9.
    OpenUrlAbstract/FREE Full Text
  92. Nieda M, Okai M, Tazbirkova A, et al. Therapeutic activation of Vα24+Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 2004;103:383–9.
    OpenUrlAbstract/FREE Full Text
  93. ↵
    Chang DH, Osman K, Connolly J, et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med 2005;201:1503–17.
    OpenUrlAbstract/FREE Full Text
  94. ↵
    Mattner J, Debord KL, Ismail N, et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 2005;434:525–9.
    OpenUrlCrossRefPubMed
  95. Zhou D, Mattner J, Cantu C III, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 2004;306:1786–9.
    OpenUrlAbstract/FREE Full Text
  96. ↵
    Dwek MV, Brooks SA. Harnessing changes in cellular glycosylation in new cancer treatment strategies. Curr Cancer Drug Targets 2004;4:425–42.
    OpenUrlCrossRefPubMed
  97. ↵
    Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE. Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol 2000;1:521–5.
    OpenUrlCrossRefPubMed
  98. ↵
    Terabe M, Matsui S, Noben-Trauth N, et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 2000;1:515–20.
    OpenUrlCrossRefPubMed
  99. ↵
    Ostrand-Rosenberg S, Clements VK, Terabe M, Park JM, Berzofsky JA, Dissanayake SK. Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and nonhemopoietic cells and is IFN-γ dependent. J Immunol 2002;169:5796–804.
    OpenUrlAbstract/FREE Full Text
  100. ↵
    Terabe M, Matsui S, Park JM, et al. Transforming growth factor-β production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 2003;198:1741–52.
    OpenUrlAbstract/FREE Full Text
  101. ↵
    Kawano T, Nakayama T, Kamada N, et al. Antitumor cytotoxicity mediated by ligand-activated human V α24 NKT cells. Cancer Res 1999;59:5102–5.
    OpenUrlAbstract/FREE Full Text
  102. Tahir SM, Cheng O, Shaulov A, et al. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J Immunol 2001;167:4046–50.
    OpenUrlAbstract/FREE Full Text
  103. Yanagisawa K, Seino K, Ishikawa Y, Nozue M, Todoroki T, Fukao K. Impaired proliferative response of Vα24 NKT cells from cancer patients against α-galactosylceramide. J Immunol 2002;168:6494–9.
    OpenUrlAbstract/FREE Full Text
  104. Fujii S, Shimizu K, Klimek V, Geller MD, Nimer SD, Dhodapkar MV. Severe and selective deficiency of interferon-γ-producing invariant natural killer T cells in patients with myelodysplastic syndromes. Br J Haematol 2003;122:617–22.
    OpenUrlCrossRefPubMed
  105. ↵
    Dhodapkar MV, Geller MD, Chang DH, et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med 2003;197:1667–76.
    OpenUrlAbstract/FREE Full Text
  106. ↵
    Kusmartsev S, Gabrilovich DI. Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother 2002;51:293–8.
    OpenUrlCrossRefPubMed
  107. ↵
    Serafini P, De Santo C, Marigo I, et al. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol Immunother 2004;53:64–72.
    OpenUrlCrossRefPubMed
  108. ↵
    Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 2004;4:941–52.
    OpenUrlCrossRefPubMed
  109. ↵
    Gabrilovich DI, Ciernik IF, Carbone DP. Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 1996;170:101–10.
    OpenUrlCrossRefPubMed
  110. ↵
    Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 1997;3:483–90.
    OpenUrlAbstract
  111. ↵
    Ishida T, Oyama T, Carbone DP, Gabrilovich DI. Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hemopoietic progenitors. J Immunol 1998;161:4842–51.
    OpenUrlAbstract/FREE Full Text
  112. ↵
    Almand B, Resser JR, Lindman B, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 2000;6:1755–66.
    OpenUrlAbstract/FREE Full Text
  113. ↵
    Claffey KP, Robinson GS. Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis. Cancer Metastasis Rev 1996;15:165–76.
    OpenUrlCrossRefPubMed
  114. ↵
    Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996;2:1096–103.
    OpenUrlCrossRefPubMed
  115. ↵
    Laxmanan S, Robertson SW, Wang E, Lau JS, Briscoe DM, Mukhopadhyay D. Vascular endothelial growth factor impairs the functional ability of dendritic cells through Id pathways. Biochem Biophys Res Commun 2005;334:193–8.
    OpenUrlCrossRefPubMed
  116. ↵
    Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 1999;5:2963–70.
    OpenUrlAbstract/FREE Full Text
  117. ↵
    Troy A, Davidson P, Atkinson C, Hart D. Phenotypic characterisation of the dendritic cell infiltrate in prostate cancer. J Urol 1998;160:214–9.
    OpenUrlCrossRefPubMed
  118. ↵
    Troy AJ, Summers KL, Davidson PJ, Atkinson CH, Hart DN. Minimal recruitment and activation of dendritic cells within renal cell carcinoma. Clin Cancer Res 1998;4:585–93.
    OpenUrlAbstract
  119. ↵
    Enk AH, Jonuleit H, Saloga J, Knop J. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 1997;73:309–16.
    OpenUrlCrossRefPubMed
  120. ↵
    Nestle FO, Burg G, Fah J, Wrone-Smith T, Nickoloff BJ. Human sunlight-induced basal-cell-carcinoma-associated dendritic cells are deficient in T cell co-stimulatory molecules and are impaired as antigen-presenting cells. Am J Pathol 1997;150:641–51.
    OpenUrlPubMed
  121. ↵
    Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992;356:607–9.
    OpenUrlCrossRefPubMed
  122. ↵
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52.
    OpenUrlCrossRefPubMed
  123. ↵
    Hoffmann TK, Muller-Berghaus J, Ferris RL, Johnson JT, Storkus WJ, Whiteside TL. Alterations in the frequency of dendritic cell subsets in the peripheral circulation of patients with squamous cell carcinomas of the head and neck. Clin Cancer Res 2002;8:1787–93.
    OpenUrlAbstract/FREE Full Text
  124. Della Bella S, Gennaro M, Vaccari M, et al. Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer 2003;89:1463–72.
    OpenUrlCrossRefPubMed
  125. ↵
    Wojas K, Tabarkiewicz J, Jankiewicz M, Rolinski J. Dendritic cells in peripheral blood of patients with breast and lung cancer: a pilot study. Folia Histochem Cytobiol 2004;42:45–8.
  126. ↵
    Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001;166:678–89.
    OpenUrlAbstract/FREE Full Text
  127. Salvadori S, Martinelli G, Zier K. Resection of solid tumors reverses T cell defects and restores protective immunity. J Immunol 2000;164:2214–20.
    OpenUrlAbstract/FREE Full Text
  128. ↵
    Danna EA, Sinha P, Gilbert M, Clements VK, Pulaski BA, Ostrand-Rosenberg S. Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 2004;64:2205–11.
    OpenUrlAbstract/FREE Full Text
  129. ↵
    Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 2001;166:5398–406.
    OpenUrlAbstract/FREE Full Text
  130. ↵
    Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T cell function in advanced cancer patients. Cancer Res 2001;61:4756–60.
    OpenUrlAbstract/FREE Full Text
  131. ↵
    Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 2004;172:989–99.
    OpenUrlAbstract/FREE Full Text
  132. ↵
    Otsuji M, Kimura Y, Aoe T, Okamoto Y, Saito T. Oxidative stress by tumor-derived macrophages suppresses the expression of CD3ζ chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci U S A 1996;93:13119–24.
    OpenUrlAbstract/FREE Full Text
  133. ↵
    Zea AH, Rodriguez PC, Atkins MB, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 2005;65:3044–8.
    OpenUrlAbstract/FREE Full Text
  134. ↵
    Rodriguez PC, Quiceno DG, Zabaleta J, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 2004;64:5839–49.
    OpenUrlAbstract/FREE Full Text
  135. ↵
    Bronte V, Serafini P, De Santo C, et al. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 2003;170:270–8.
    OpenUrlAbstract/FREE Full Text
  136. ↵
    Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 2005;26:111–7.
    OpenUrlCrossRefPubMed
  137. ↵
    Kjaergaard J, Peng L, Cohen PA, Shu S. Therapeutic efficacy of adoptive immunotherapy is predicated on in vivo antigen-specific proliferation of donor T cells. Clin Immunol 2003;108:8–20.
    OpenUrlCrossRefPubMed
  138. ↵
    Lou Y, Wang G, Lizee G, et al. Dendritic cells strongly boost the antitumor activity of adoptively transferred T cells in vivo. Cancer Res 2004;64:6783–90.
    OpenUrlAbstract/FREE Full Text
  139. ↵
    Ye QW, Mokyr MB. Cyclophosphamide-induced appearance of immunopotentiating T-cells in the spleens of mice bearing a large MOPC-315 tumor. Cancer Res 1984;44:3873–9.
    OpenUrlAbstract/FREE Full Text
  140. Berd D, Maguire HC, Jr., Mastrangelo MJ. Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide. Cancer Res 1984;44:5439–43.
    OpenUrlAbstract/FREE Full Text
  141. Mokyr MB, Dray S. Interplay between the toxic effects of anticancer drugs and host antitumor immunity in cancer therapy. Cancer Invest 1987;5:31–8.
    OpenUrlPubMed
  142. Claessen AM, Valster H, Bril H, Steerenberg PA, Tan BT, Scheper RJ. Tumor regression and induction of anti-tumor immunity by local chemotherapy of guinea-pigs bearing a line-10 hepatocarcinoma. Int J Cancer 1991;47:626–32.
    OpenUrlPubMed
  143. ↵
    Matar P, Rozados VR, Gervasoni SI, Scharovsky GO. Th2/Th1 switch induced by a single low dose of cyclophosphamide in a rat metastatic lymphoma model. Cancer Immunol Immunother 2002;50:588–96.
    OpenUrlCrossRefPubMed
  144. ↵
    Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003;3:666–75.
    OpenUrlCrossRefPubMed
  145. ↵
    Overwijk WW. Breaking tolerance in cancer immunotherapy: time to ACT. Curr Opin Immunol 2005;17:187–94.
    OpenUrlCrossRefPubMed
  146. ↵
    Dudley ME, Wunderlich JR, Robbins PJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850–4.
    OpenUrlAbstract/FREE Full Text
  147. ↵
    Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother 2002;25:243–51.
  148. ↵
    Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346–57.
    OpenUrlAbstract/FREE Full Text
  149. ↵
    Rosenberg SA, Dudley ME. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci U S A 2004;101:14639–45.
    OpenUrlAbstract/FREE Full Text
  150. Robbins PF, Dudley ME, Wunderlich J, et al. Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 2004;173:7125–30.
    OpenUrlAbstract/FREE Full Text
  151. ↵
    Zhou J, Dudley ME, Rosenberg SA, Robbins PF. Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J Immunother 2005;28:53–62.
  152. ↵
    Frankel AE, Powell BL, Lilly MB. Diphtheria toxin conjugate therapy of cancer. Cancer Chemother Biol Response Modif 2002;20:301–13.
    OpenUrlPubMed
  153. ↵
    Kreitman RJ. Recombinant immunotoxins for the treatment of haematological malignancies. Expert Opin Biol Ther 2004;4:1115–28.
    OpenUrlCrossRefPubMed
  154. ↵
    Greene WC, Leonard WJ. The human interleukin-2 receptor. Annu Rev Immunol 1986;4:69–5.
    OpenUrlCrossRefPubMed
  155. ↵
    Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001;19:565–94.
    OpenUrlCrossRefPubMed
  156. ↵
    Grohmann U, Orabona C, Fallarino F, et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002;3:1097–101.
    OpenUrlCrossRefPubMed
  157. ↵
    Fallarino F, Grohmann U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206–12.
    OpenUrlCrossRefPubMed
  158. ↵
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734–6.
    OpenUrlAbstract
  159. ↵
    Espenschied J, Lamont J, Longmate J, et al. CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. J Immunol 2003;170:3401–7.
    OpenUrlAbstract/FREE Full Text
  160. ↵
    Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003;100:4712–7.
    OpenUrlAbstract/FREE Full Text
  161. ↵
    Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003;100:8372–7.
    OpenUrlAbstract/FREE Full Text
  162. ↵
    Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043–53.
    OpenUrlAbstract/FREE Full Text
  163. ↵
    Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793–800.
    OpenUrlCrossRefPubMed
  164. ↵
    Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med 2003;81:281–7.
    OpenUrlPubMed
  165. ↵
    Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 2005;54:307–14.
    OpenUrlCrossRefPubMed
  166. ↵
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002;99:12293–7.
    OpenUrlAbstract/FREE Full Text
  167. Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 2003;9:562–7.
    OpenUrlCrossRefPubMed
  168. ↵
    Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005;65:1089–96.
    OpenUrlAbstract/FREE Full Text
  169. ↵
    Tyagi P. First-line treatment with bevacizumab and paclitaxel prolongs progression-free survival in metastatic breast cancer. Clin Breast Cancer 2005;6:105–7.
  170. Tuma RS. Success of bevacizumab trials raises questions for future studies. J Natl Cancer Inst 2005;97:950–1.
    OpenUrlFREE Full Text
  171. ↵
    Midgley R, Kerr D. Bevacizumab—current status and future directions. Ann Oncol 2005;16:999–1004.
    OpenUrlAbstract/FREE Full Text
  172. ↵
    Mulcahy MF, Benson AB III. Bevacizumab in the treatment of colorectal cancer. Expert Opin Biol Ther 2005;5:997–1005.
    OpenUrlCrossRefPubMed
  173. ↵
    Hwu P, Du MX, Lapointe R, Do M, Taylor MW, Young HA. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 2000;164:3596–9.
    OpenUrlAbstract/FREE Full Text
  174. ↵
    Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003;9:1269–74.
    OpenUrlCrossRefPubMed
  175. ↵
    De Santo C, Serafini P, Marigo I, et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U S A 2005;102:4185–90.
    OpenUrlAbstract/FREE Full Text
  176. ↵
    Bronte V, Kasic T, Gri G, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 2005;201:1257–68.
    OpenUrlAbstract/FREE Full Text
  177. ↵
    Thomsen LL, Miles DW. Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev 1998;17:107–18.
    OpenUrlCrossRefPubMed
  178. ↵
    Ekmekcioglu S, Tang CH, Grimm EA. NO news is not necessarily good news in cancer. Curr Cancer Drug Targets 2005;5:103–15.
    OpenUrlCrossRefPubMed
  179. Liu Y, Van Ginderachter JA, Brys L, De Baetselier P, Raes G, Geldhof AB. Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells. J Immunol 2003;170:5064–74.
    OpenUrlAbstract/FREE Full Text
  180. ↵
    Blesson S, Thiery J, Gaudin C, et al. Analysis of the mechanisms of human cytotoxic T lymphocyte response inhibition by NO. Int Immunol 2002;14:1169–78.
    OpenUrlAbstract/FREE Full Text
  181. Bronte V, Serafini P, Mazzoni A, Segal DM, Zanovello P. l-Arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol 2003;24:302–6.
    OpenUrlCrossRefPubMed
  182. ↵
    Bronte V, Zanovello P. Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 2005;5:641–54.
    OpenUrlCrossRefPubMed
  183. ↵
    Berendt MJ, North RJ. T-cell-mediated suppression of anti-tumor immunity: an explanation for progressive growth of an immunogenic tumor. J Exp Med 1980;151:69–80.
    OpenUrlAbstract/FREE Full Text
  184. Bursuker I, North RJ. Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity. J Exp Med 1984;159:1312–21.
    OpenUrlAbstract/FREE Full Text
  185. North RJ, Bursuker I. Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2− suppressor T cells down-regulate the generation of Ly-1−2+ effector T cells. J Exp Med 1984;159:1295–311.
    OpenUrlAbstract/FREE Full Text
  186. ↵
    North RJ, Awwad M. T cell suppression as an obstacle to immunologically-mediated tumor regression: elimination of suppression results in regression. Prog Clin Biol Res 1987;244:345–58.
    OpenUrlPubMed
  187. ↵
    Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells. Semin Immunol 2004;16:89–98.
    OpenUrlCrossRefPubMed
  188. ↵
    Levings MK, Sangregorio R, Sartirana C, 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 2002;196:1335–46.
    OpenUrlAbstract/FREE Full Text
  189. ↵
    von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol 2005;6:338–44.
    OpenUrlCrossRefPubMed
  190. ↵
    Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002;20:29–53.
    OpenUrlCrossRefPubMed
  191. ↵
    Dumont N, Arteaga CL. Targeting the TGFβ signaling network in human neoplasia. Cancer Cell 2003;3:531–6.
    OpenUrlCrossRefPubMed
  192. ↵
    Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004;4:762–74.
    OpenUrlCrossRefPubMed
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Clinical Cancer Research: 12 (16)
August 2006
Volume 12, Issue 16

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Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms
Gregory Lizée, Laszlo G. Radvanyi, Willem W. Overwijk and Patrick Hwu
Clin Cancer Res August 15 2006 (12) (16) 4794-4803; DOI: 10.1158/1078-0432.CCR-06-0944
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