Current Cancer Drug Targets

ISSN: 1568-0096

Current Cancer Drug Targets
Volume 7, Number 1, February 2007

Contents
Molecular Mechanisms and Therapeutic Reversal of Immune Suppression in Cancer
Guest Editor: Dmitry I. Gabrilovich


Editorial Pp. 1


Mechanisms of T Cell Tolerance and Suppression in Cancer Mediated by Tumor-Associated Antigens and Hormones Pp. 3-14
Adam J. Adler
[Abstract] [Full text article]


Costimulation, Coinhibition and Cancer Pp. 15-30
Brant A. Inman, Xavier Frigola, Haidong Dong and Eugene D. Kwon
[Abstract] [Full text article]


Indoleamine 2,3-Dioxygenase in Immune Suppression and Cancer Pp. 31-40
Alexander J. Muller and George C. Prendergast
[Abstract] [Full text article]


Cellular and Molecular Mechanisms of Tumor-Induced T-Cell Tolerance Pp. 41-53
Pedro Horna and Eduardo M. Sotomayor
[Abstract] [Full text article]


T Cell Costimulatory and Inhibitory Receptors as Therapeutic Targets for Inducing Anti-Tumor Immunity Pp. 55-70
Jeurgen Foell, Becker Hewes and Robert S. Mittler
[Abstract] [Full text article]


Targeting of Jak/STAT Pathway in Antigen Presenting Cells in Cancer Pp. 71-77
Yulia Nefedova and Dmitry I. Gabrilovich
[Abstract] [Full text article]


Mechanisms Used by Human Papillomaviruses to Escape the Host Immune Response Pp. 79-89
Shreya Kanodia, Laura M. Fahey and W. Martin Kast
[Abstract] [Full text article]


General Articles


Small Molecule Inhibitors of Stat3 Signaling Pathway Pp. 91-107
Jinxia Deng, Fedora Grande and Nouri Neamati
[Abstract] [Full text article]


Anatomic Site-Related Expression of Cancer-Associated Molecules in Ovarian Carcinoma Pp. 109-120
Ben Davidson
[Abstract] [Full text article]




Abstracts


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Editorial

Since it has become clear that tumor can be recognized and eliminated by the host immune system, two main questions have confronted researchers and physicians: why the immune system does not prevent tumor progression, and how to manipulate the immune system to achieve tumor eradication. The last 20 years have brought a clear realization that one of the major mechanisms of tumor escape and one of the major factors limiting the clinical success of cancer vaccines is the inadequate function of the host immune system in tumor-bearing hosts.

Intensive studies in this field have resulted in the discovery of numerous cellular mechanisms of immune suppression in cancer, including ubiquitous regulatory T cells, myeloid-derived suppressive cells, tumor-infiltrating macrophages. These cells in combination with tumor cells suppress T-cell responses via suppressive surface molecules like CTLA-4, PD-1, PD-2, production of inhibitory cytokines like IL-10, TGF-β, VEGF, etc., depletion of T cells of tryptophan and arginine, release of reactive oxygen species and nitric oxide and many others. These findings form the foundation of the approaches to improve immune response in cancer, and enhance the effects of cancer vaccines. This issue of the journal presents articles on the different aspects of this problem. Readers will find detailed analysis of cellular and molecular mechanisms of immune non-responsiveness in cancer. These mechanisms include the role of oncogenic viruses, different signaling pathways and surface molecules, hormones, and aminoacids in the regulation of the immune response in cancer. Special attention is given to the discussion of novel methods of therapeutic targeting of these mechanisms. Elimination of negative signaling in the tumor-bearing host may open a new avenue for therapeutic intervention, able to improve the outcome.

However, these reviews also point out important conceptual problems in modern tumor immunology. Most of the described mechanisms are not tumor-specific. The paradox is that despite the apparent presence of a large number of potent immune suppressive factors, neither tumor-bearing mice nor cancer patients are immune compromised. Even at relatively advanced stages of cancer, their immune system retains the ability to respond to non-specific stimulation with viral and bacterial antigens or lectins. At the same time, tumor-specific immune response is repressed. This raises a question about the role of immune suppressive factors in tumor non-responsiveness. It appears that the understanding of the mechanisms of tumor escape requires identification of the precise role of tumor-specific immune tolerance vis-à-vis non-specific immune suppression. Reviews included in this issue of the journal will cover the mechanism and importance of tumor-specific immune tolerance in the inability of the immune system to develop and maintain antitumor immune responses. The preponderance of scientific evidence may suggest that in peripheral lymphoid organs, tumor-specific T-cell tolerance is more likely to be responsible for tumor escape than non-specific immune suppression. A different situation may exist inside the tumor. It is likely that non-specific immune suppression provided by tumor microenvironment may play a very significant role in the inability of cytotoxic T cells to recognize and eliminate a tumor. However, it is still unclear whether T cells are rendered non-responsive inside a tumor or if they migrate to the tumor site already being tolerized in peripheral lymphoid organs. There are no clear answers to these questions. Interested readers may form their own opinions after reading the articles in this issue that present analysis of available data.

The targeting of negative regulatory pathways discussed in detail in this issue of the journal also raises a dilemma. Negative regulatory mechanisms are essential in preventing excessive immune responses to foreign antigens and autoimmune abnormalities. It is logical that the elimination of these factors will result in the activation of the immune system. The question is whether this activation will benefit the patient or not. The removal of negative breaks would result in an accumulation of T cells reactive to any available antigens. Most of the viral and bacterial antigens are much stronger immunogens than self-antigen presented in tumors. The proportion of tumor-specific T cells among this pool of reactive T cells could be quite small. They can still be easily detected since investigators are specifically looking for these cells. However, whether they are sufficient to prevent tumor progression or not, is not known. Current clinical studies will help to address this question.

We are witnessing now new exciting developments in the field of tumor immunology. We have become more sophisticated in our approach to targeting immunosuppressive mechanisms. However, many critical questions remain unresolved. The collection of reviews presented in this issue of the journal provides readers with detailed unbiased analyses of the different mechanisms of immune suppression in cancer and novel approaches to their correction. I hope they will help to stimulate further research in this fascinating field.

Dmitry I. Gabrilovich, MD, PhD
Professor of Interdisciplinary Oncology and
Molecular Medicine, Member, H. Lee
Moffitt Cancer Center, University of South Florida,
MRC 2067, 12902 Magnolia Dr. Tampa, FL 33612, USA
Ph.: 813-903-6863, Fax: 813-745-1328;
E-mail: dgabril@moffitt.usf.edu


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Mechanisms of T Cell Tolerance and Suppression in Cancer Mediated by Tumor-Associated Antigens and Hormones
Adam J. Adler

[Full text article]

Despite recent advances in vaccine technology, vaccines designed to elicit T cell-based anti-tumor immunity have only achieved partial success in the clinic. The underlying reason probably stems in part from the ability of tumors to repress cognate T cell responses, which appears to operate at two separate levels. In some cases, tumors engage a variety of immunosuppressive pathways that inhibit primed effector T cells from functioning when they enter the tumor microenvironment. Some of these immunosuppressive mechanisms include the production of cytokines such as TGF-β and the recruitment or differentiation of regulatory T cells. In contrast, other types of tumors induce a systemic impairment in the function of tumor-reactive T cells (i.e., tolerance). Tolerance to tumor antigens can be mediated through the same mechanisms that induce T cell tolerance to normal self-antigens in order to avoid autoimmunity, and can develop not only towards differentiation antigens that are expressed on both tumors as well as on the normal tissues from which they derive, but can also develop rapidly towards tumor-specific antigens. Additionally, both naive and effector T cells are susceptible to tolerization, suggesting that tolerance can potentially dampen both the priming and effector phases of anti-tumor T cell responses. Certain hormones can influence both tumorigenesis as well as T cell function and tolerance, and thus hormonal therapies could potentially impact the efficacy of T cell-based therapies. An example of this type of interaction that will be discussed in detail is the relationship between androgens and prostate cancer.


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Costimulation, Coinhibition and Cancer
Brant A. Inman, Xavier Frigola, Haidong Dong and Eugene D. Kwon

[Full text article]

The immune system is an important defense mechanism against cancer and is often dysfunctional in patients with malignancies. The central regulator of the anti-cancer adaptive immune response is the T lymphocyte. T lymphocyte activation requires the completion of a carefully orchestrated series of specific steps that can be preempted or disrupted by any number of critical events. Particularly important is the provision of a costimulatory signal, the binding of accessory molecules on the antigen presenting cell to receptors on the T lymphocyte. Though costimulatory signals were traditionally envisioned as T lymphocyte-activating events, recent discoveries have highlighted their duality: they can be either stimulatory (costimulation) or inhibitory (coinhibition). In this article we review costimulation and coinhibition as potential targets for cancer therapy. We begin by presenting a general framework for thinking about the immune system in the context of cancer. Our discussion then bridges the various aspects of immune dysfunction seen in cancer with the presence of coinhibitory (ex: PD-1, PD-L1, CTLA-4, BTLA) and costimulatory (ex: CD28, ICOS, 4-1BB, CD40, OX40, CD27) signaling. Lastly, we develop a model of cancer-related immune dysfunction that parallels the concept of immunoediting. Throughout the article we emphasize clinically relevant research often applicable—but not limited—to the example of renal cell carcinoma.


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Indoleamine 2,3-Dioxygenase in Immune Suppression and Cancer
Alexander J. Muller and George C. Prendergast

[Full text article]

The extrahepatic enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan degradation in the first and rate-limiting step towards biosynthesis of the central metabolic co-factor nicotinamide adenine dinucleotide (NAD). While this pathway has been known for decades, the actual physiological role for IDO in
mammals remained obscure, because (i.) most cell types do not express the downstream enzymes in the NAD biosynthesis pathway and (ii.) mammals salvage rather than synthesize NAD to meet their metabolic needs. An immunological role for IDO was hinted at with the observation that IDO expression is stimulated by interferon- γ and subsequently confirmed by the discovery of its physiological importance in protecting the fetus from maternal immunity. Similarly, elevations in tryptophan catabolism in cancer patients were known since the 1950s, but the basis and meaning of this phenomenon were uncertain until it was shown that IDO, which is commonly elevated in tumors and draining lymph nodes, suppresses T cell immunity in the tumor microenvironment. Indeed, by creating peripheral tolerance to tumor antigens, IDO can undermine immune responses that thwart tumor cell survival in the context of an underlying inflammatory environment that facilitates tumor outgrowth. In preclinical studies, small molecule inhibitors of IDO compromise this mechanism of immunosuppression and strongly leverage the efficacy of a variety of classical chemotherapeutic agents, supporting the clinical development of IDO inhibitors as a therapeutic goal. This essay summarizes key findings that implicate IDO as an important mediator of peripheral tolerance and discusses the development of anti-cancer modalities that incorporate the use of IDO inhibitors.


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Cellular and Molecular Mechanisms of Tumor-Induced T-Cell Tolerance
Pedro Horna and Eduardo M. Sotomayor

[Full text article]

The spontaneous interaction between tumor cells and the immune system has been shown to result in reciprocal changes leading to a less immunogenic tumor and immune cells less capable or unable to mount an effective response against a growing malignancy. Although several mechanisms have been proposed to account for the ability of tumor cells to render immune cells less efficient, one that has gained particular attention relates to the recognition of tumor antigens by T-cells, a process that unfortunately leads to the induction and establishment of antigen-specific T-cell tolerance rather than T-cell priming. Here, we present the experimental and clinical evidence that help identify this remarkable barrier that the immune system itself and more specifically its mechanisms of tolerance induction has imposed to our efforts to effectively harness the immune system against tumors. In particular, we will discuss the central role of bone marrow-derived antigen-presenting cells (APCs) in the induction of this state of T-cell unresponsiveness and the potential role of the tumor microenvironment in determining the tolerogenic properties of these APCs. Finally, we provide information on receptor-ligands and intracellular signaling pathways that given their role in influencing the inflammatory properties of APCs are being exploited as targets to revert mechanisms of T-cell unresponsiveness in cancer.


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T Cell Costimulatory and Inhibitory Receptors as Therapeutic Targets for Inducing Anti-Tumor Immunity
Jeurgen Foell, Becker Hewes and Robert S. Mittler

[Full text article]

Central to the normal function of the immune system is its ability to distinguish between self and non-self since failure to do so could provoke the onset of autoimmune disease. To avoid this possibility, the immune system employs several processes that include, negative selection, peripheral tolerance, and limiting DC antigen priming of naïve T cells to the lymph nodes. Naïve T cells must receive two independent signals from these antigen-presenting cells (APC) that other cells cannot provide if they are to become productively activated. The first is antigen-specific and occurs when T cell antigen receptors encounter the appropriate antigen-MHC complex on the APC - Signal 1. A second, antigen-independent signal is delivered through a T cell costimulatory molecule that engages its APC-expressed ligands - Signal 2. In the absence of a costimulatory signal T cells typically enter a state of anergy. Furthermore, the extent to which T cell activation occurs can be held in check through specific inhibitory receptors expressed on T cells. Understanding the basic mechanisms of how T cell activation is regulated has led to the development of therapeutic approaches for targeting T cell costimulatory and inhibitory pathways for turning on, or preventing the turning off immune responses in subjects with cancer. In this review we will discuss several T cell costimulatory and inhibitory pathways known to influence the development of anti-tumor immunity and how experimental manipulation of these signaling pathways has led to the generation of protective, or curative anti-tumor immunity in mice and humans.


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Targeting of Jak/STAT Pathway in Antigen Presenting Cells in Cancer
Yulia Nefedova and Dmitry I. Gabrilovich

[Full text article]

One of the major mechanisms of tumor escape is the inability of antigen presenting cells (APC), and specifically the most potent APC dendritic cells (DC), to induce potent antitumor immune response. The defects in APC are caused by the variety of tumor-derived factors. In this review we will discuss recent findings which indicate that the members of the family of signal transducers and activators of transcription (STATs), and more specifically STAT3, could be responsible for the abnormal DC differentiation and function in cancer. The different approaches to pharmacological regulation of this pathway and their effects on DC function and antitumor immune responses will be discussed.


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Mechanisms Used by Human Papillomaviruses to Escape the Host Immune Response
Shreya Kanodia, Laura M. Fahey and W. Martin Kast

[Full text article]

The greatest risk factor for the development of cervical and other cancers that have been linked to the human papillomavirus (HPV) family is the persistence of the virus. To persist for the decades required to develop HPV-related cancers, the virus must escape host immunity. HPV is a simple DNA virus that has evolved to escape immune attack by a combination of stealth and interference. This review focuses on the mechanisms by which HPV can evade recognition by the host immune system.


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Small Molecule Inhibitors of Stat3 Signaling Pathway
Jinxia Deng, Fedora Grande and Nouri Neamati

[Full text article]

Constitutive activation of the Signal Transducers and Activators of Transcription 3 (Stat3) meditated signaling pathway is very important for cell growth and survival. Compelling evidence from mechanistic studies with antisense, RNA interference (RNAi), peptides, and small molecular inhibitors indicate that blocking Stat3 signaling can lead to successful suppression of tumor cell growth and apoptosis. Thus, Stat3 is an attractive molecular target for the development of novel cancer therapeutics. In this article, we present the first comprehensive review focusing on small molecule inhibitors that effectively block the Stat3 signaling pathway. These inhibitors, from a structural point of view, are divided into five classes of compounds. They include (1) natural products and derivatives, such as curcumin, resveratrol and others, (2) tyrphostins, (3) platinum-containing complexes, (4) peptidomimetics, and (5) azaspiranes. Some compounds may have multiple targets including Stat3 protein, therefore these compounds need further optimization and validation. The purpose of this review is to provide a resource for researchers interested in Stat3 targeted small molecules which will be beneficial for database development and template design for future drug development.


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Anatomic Site-Related Expression of Cancer-Associated Molecules in Ovarian Carcinoma
Ben Davidson

[Full text article]

Ovarian cancer presents as disseminated disease in the majority of cases. Tumor metastasis to the peritoneal and/or pleural cavity is evident in two-thirds of cases at diagnosis and relapse is most often detected at this anatomic site. Despite the fact that the primary tumor is amenable to surgical removal in the majority of cases, ovarian cancer research, including the evaluation of therapeutic targets, has concentrated on primary disease. In recent years, we analyzed the site-dependent expression of cancer-associated and regulatory molecules in primary tumors, effusions and solid metastases. Our data show that some molecules (e.g., Ets transcription factors) are expressed at all anatomic sites in ovarian carcinoma and that their expression in primary and metastatic disease is associated with poor prognosis. However, the majority of molecules (e.g., cadherins, integrins, and nerve growth factor receptors) are differentially expressed along tumor progression and have different prognostic value depending on the organ sampled. Specifically, cancer-associated molecules with a well-characterized clinical significance in solid tumors (e.g., matrix metalloproteinases) have no such role in effusions. Finally, a growing number of molecules are differentially expressed in primary diagnosis (pre-chemotherapy) and disease recurrence (post-chemotherapy) specimens, reflecting the effect of disease progression and chemotherapy. This review will present the current knowledge in this area.