Current Molecular Medicine - Volume 9, Issue 6, 2009

Considerable progress has been made in our understanding of host immune responses to cancer. This includes identification of antigens overexpressed on human tumors and antigen epitopes recognized by the cellular arm of the immune system (CD4+, CD8+ T and NK T-cell populations); identification and characterization of antigen presenting cells (e.g., dendritic cells); co-stimulatory requirements for effective antigen presentation; the role of various cytokines and their receptors in regulating immune responses; understanding of signal transduction pathways that control T cells and APC differentiation; effector cell function and survival; the role of tumor stroma and inflammation on cancer development and the role of suppressor cells (e.g. T-regulatory cells, myeloid-derived suppressor cells, etc.) in tumor development and evading the immune system. The literature contains reports on large number of cancer vaccines and immunotherapy approaches based on the above concepts that are being tested in pre-clinical and clinical trials to treat cancer. This special issue of the journal covers the latest advances in the field of cancer immunology and immunotherapy and discusses host responses against tumors. In the first chapter Berzofsky and Terabe discuss two different types of NKT cells that counter-regulate each other in cancer and form a new immunoregulatory axis. The balance along this axis could modulate immunity to tumors, infections, autoimmune diseases and responses to cancer vaccines. In the second chapter, Petrausch and colleagues elegantly describe the role of regulatory T cells in regulating immunity to self, allo-antigens, infectious agents, the fetus and cancer. T-regs can suppress the immune response by suppression of effector T cell function, antigen-specific priming of naive T cells or modulation of the function of antigen-presenting cells. These authors describe strategies for modulating and eliminating T-regs in the context of cancer vaccines. In the third chapter, Voskens and colleagues discuss important aspects of peptide vaccination offer strategies to enhance success and summarize aspects of CD4+ T cell help in peptide-based cancer vaccine strategies. They also discuss potential strategies to improve peptide based cancer vaccines through the generation of both HLA class I and class II vaccine-specific immune responses. The fourth and fifth chapters cover the role of tumor vascular endothelial cells and VEGF, which is a prominent tumor cytokine that manipulates both angiogenesis and tumor immunity to enhance tumor survival. Varney et al. discuss involvement of the tumor microenvironment and production of inhibitory factors such as VEGF-c in tumor angiogenesis and lymphangiogenesis. Johnson et al. describe the emerging role of VEGF in the immune system as well as how therapy directed against VEGF may target multiple aspects of cancer immunology. Methods to inhibit tumor induced angiogenesis, when combined with other approaches, may be a powerful strategy for cancer therapy. Chapters six and seven focus on potent antigen-presenting cells, e.g., dendritic cells. Srivastava and Khar review a pivotal role of DC to attract lymphocytes to control immunological homeostatis through specific receptors. In addition to their antigen presentation functions, these receptors are also believed to induce direct cytotoxicity. Murthy et al. review clinical considerations for the development of dendritic cell-based cancer vaccine protocols. These authors recommend following common standards for monitoring and reporting of DC-based clinical trials to fully realize the potential of this approach. In chapter eight, Puri et al. review the identification and characterization of the TH2 cytokine IL-4 receptor in a variety of human cancers as a tumor antigen and a target for receptor-directed anti-cancer therapy. These authors discuss targeting of IL-4 receptors with a cytotoxin that consists of circularly permuted IL-4 and truncated Pseudomonas exotoxin. Three completed phase 1/ 2 clinical trials of this cytotoxin are summarized. In chapter nine, Strober et al. review their elegant work on the IL-4-related cytokine, IL-13, and the role of high affinity IL-13 receptor (IL-13Rα2) in the development of gastrointestinal fibrosis and cancer surveillance. They demonstrate for the first time that IL-13 can signal through IL-13Rα2 involving the AP-1 pathway and induce TGF-β1 production leading to fibrosis.

NKT cells are true T cells that serve as a bridge between the innate and adaptive immune system, acting as first responders. They recognize lipid antigens rather than peptides, and respond to these when presented by a non-classical class I MHC molecule, CD1d. NKT cells can play a pathogenic role in asthma or a protective role against several autoimmune diseases, in part based on their cytokine profile. In cancer, they can play opposite roles, contributing to anti-tumor immunity or suppressing it. The protective NKT cells were found to be primarily type I NKT cells defined by use of a semi-invariant T cell receptor involving Vα14Jα18 in mice and Vα24Jα18 in humans and responding to α-galactosylceramide, and the most protective were among the minority that are CD4-. The suppressive NKT cells were found to be CD4+ and to be primarily type II NKT cells, that have diverse T-cell receptors and respond to other lipids. Further, the type I and type II NKT cells were found to counter-regulate each other, forming a new immunoregulatory axis. This axis may have broad implications beyond cancer, as NKT cells play a role in steering other adaptive immune responses. The balance along this axis could affect immunity to tumors and infectious diseases and responses to vaccines.

Since multiple lines of experimental and clinical data clearly identified regulatory T cells as an integral part of the immune response, these cells have become a major focus of investigation in tumor immunology. Regulatory T cells are in place to dampen ongoing immune responses and to prevent autoimmunity, but they also have profound effects in blocking therapeutic anti-tumor activity. Therefore regulatory T cells are seen as a major hurdle that must be overcome in order for cancer immunotherapy to reach its therapeutic potential. Regulatory T cells are heterogeneous with sub-populations that exhibit distinct functional features. Here we will review the individual sub-populations in regards to their mode of action and their potential impact on blocking anti-tumor immunity. Approaches to measure function and frequency of regulatory T cells in model systems and clinical trails will be discussed. Finally, we will describe possible ways to interfere with regulatory T cell-mediated immune suppression with the focus on recent pre-clinical and clinical findings.

In the vast majority of studies conducted to date, activation of cancer-specific T cell immunity through peptide-based immunization has failed to induce objective tumor regression. This failure is particularly troublesome given that these vaccines often stimulate T cell responses. In this review, we attempt to understand the relative failure of peptide cancer vaccines to achieve clinically meaningful responses. In the first part of the review, we discuss specific hurdles to successful application of synthetic peptide-based vaccines including patient variability and epitope selection. In the second part of this review, we summarize the importance of CD4+ T cell help in peptide-based vaccine strategies and offer a potential strategy to improve peptide-based vaccines through the generation of both HLA class I and class II vaccine specific-immune responses.

Tumor-induced immunosuppression is a fundamental problem in cancer immunotherapy and can occur by a variety of cellular and molecular mechanisms, affecting all arms of the immune system. Tumorproduced or elicited factors have been shown to inhibit antigen-specific immune effector function as well as impairment of the development, recruitment and maturation of dendritic cells (DCs) and T cells. A better understanding of the cross-talk between tumors and tumor-associated DCs and T cells is necessary to develop novel approaches for cancer immunotherapy. The recruitment of DCs to tumors, antigen processing and presentation, and migration of antigen-loaded DCs to secondary lymphoid organs are perturbed in tumorbearing hosts. The ability of tumor-associated DCs to induce an anti-tumor response may be prevented by the tumor microenvironment due to inhibitory factors such as vascular endothelial growth factor (VEGF)-C, which are also known to regulate tumor angiogenesis and lymphangiogenesis. Strategies to inhibit tumor-induced angiogenesis and immunosuppression provide therapeutic approaches with the potential for synergism. In this review we will discuss the possibilities of developing novel approaches to concurrently inhibit angiogenesis, inhibit lymphangiogenesis, eliminate tumor-induced immunosuppression and augment the anti-tumor immune as potent multi-modality therapeutic strategies for metastatic cancer.

Vascular endothelial growth factor (VEGF), known as a primary mediator of tumor-induced angiogenesis, is now understood to have a role in tumor-associated immunosuppression. Initially, VEGF was identified to alter the growth and maturation of the immature granulocyte-macrophage progenitors, and more recently it has been noted that it prevents dendritic cell (DC) precursors from developing into mature, antigenpresenting DC. VEGF is associated with recruitment of macrophages to the tumor stroma and VEGF inhibition of myeloid progenitor maturation is associated with the development tumor associated macrophages (TAM) which possess immunosuppressive capacity as well. Therapies intended to inhibit VEGF or VEGF receptors have demonstrated improved anti-tumor immunity and enhanced responses to cancer vaccines.

DCs are recognized as the pivotal group of lymphocytes, which induce a variety of antitumor immune responses. Enduring professional antigen presenting cells, DCs eminence to induce adaptive antitumor immune response was exploited, which showed promising results in DCs-based phased clinical studies. Nevertheless, DCs also influence other immune cells to induce multiple arms of immune system to cure cancer. Recently, direct cytotoxic capacity of DCs has been demonstrated in several studies. Altogether DCs hold a strong link between innate and adaptive immune responses. DCs are known to kill tumor cells, phagocytose immunogenic substrates and present a wide variety of antigens to prime T cells to induce concerted antitumor responses. These functional aspects of DCs are dependent on the receptors that participate in the stimulation of DCs. In this review, we have discussed these receptors that are known to induce direct cytotoxicity as well as the receptors that greatly influence their antigen presentation functions. Thus DCs are turning out to be an important cell type in cancer immunotherapy.

Since the first reported clinical trial of Dendritic Cell Vaccine (DCV) in cancer in the mid nineties, few hundred clinical trials have been initiated and it was projected that over 3000 patients would be treated in DCV clinical trials by 2008. Despite extensive data to establish its safety, DCV remains an investigational approach, highlighting the need to undertake more meaningful proof of principle studies and more importantly, well designed and well conducted large efficacy trials. As opposed to phase I and II trials of new chemical entities where pharmacokinetics, maximum tolerated dose, toxicity profile and dose response effects are the primary concerns, for DCV the pertinent issues are quite different. Based on a critical appraisal of the available literature, we examine the important host, tumour and treatment considerations and specific issues related to the design and conduct of DCV based clinical trials. Impact of patient related factors such as extremes of age, host immune competence and the host HLA type on the host immune response to DCV and using these parameters either as a selection criteria or a stratification parameter is discussed. Clinical trials of DCV also need to consider selection of tumour types and their antigenic expression better suited for DCV. The influence of previous or concurrent cytotoxic treatment and corticosteroid which could influence the yield of monocytes in leukapheresis or the host immune response to DCV requires consideration in the clinical trial design. Safety issues of DCV in pregnant women, children and in those with inherent of acquired immune disorders are discussed.

Despite advances in biomedical sciences, the prognosis of patients with brain tumors remains poor. Effective treatment is lacking for these central nervous system (CNS) cancers. Targeted immunotoxins are a new class of therapeutic approaches that have emerged for the treatment of human cancers. In this approach, tumor antigen or cell surface receptor is targeted by a chimeric fusion protein consisting of an antibody or a ligand and a suicidal gene or toxin to kill tumor cells. In that regard, receptors for interleukin (IL)-4 (IL-4R) have been identified to be overexpressed on a variety of human CNS tumor cell lines and tissue samples including meningioma. In various studies, high grade brain tumor specimens and malignant brain tumor cell lines have been shown to overexpress high-affinity IL-4R, while normal brain samples or cell lines expressed lower levels of these receptors. The structures of IL-4R on CNS tumors have been studied, which demonstrate that these cells express predominantly type II IL-4R. These receptors are functional as IL-4 can cause signal transduction, inhibit growth of some tumor cell lines and increase expression of major histocompatibility antigens and intracellular adhesion molecular-1 (ICAM-1) on some tumor cells lines. To target IL-4R, a chimeric fusion protein composed of IL-4 and truncated Pseudomonas exotoxin has been developed. This cytotoxin is highly cytotoxic to IL-4R positive tumors in vitro and has been reported to be highly effective in preclinical animal model of human brain cancer. Several Phase I/II clinical trials for treatment of IL-4R positive cancers have been completed. This review article will summarize pre-clinical and clinical development of IL- 4PE cytotoxin.

The IL-13Rα2 receptor is a high affinity receptor for IL-13 that is used only by IL-13 and is quite distinct from the well known IL-13Rα1 receptor that IL-13 shares with IL-4. It was widely considered to be a secreted receptor that is devoid of signaling activity and functional only as a decoy receptor that retarded signaling via IL-13Rα1. In recent studies, however, it was shown to be capable of robust signaling that results in production of TGF-β1 and through the latter cytokine, the induction of fibrosis occuring in various experimental inflammatory states. Thus, in initial studies, IL-13 signaling via IL-13Rα2 was shown to play an important role in the fibrosis developing in both oxazolone colitis and bleomycin-induced pulmonary fibrosis; later, it was also shown to be critical to the development of fibrosis in a model of chronic colitis induced by trinitrobenzene sulphonic acid (TNBS). These studies suggest that blockade of IL-13 or IL-13Rα2 signaling might be an excellent target for the prevention of inflammation-associated fibrosis. A second role of IL-13 signaling via IL-13Rα2 is in tumor immune surveillance. Thus, in the relevant studies it was shown that NKT cells stimulated by tumor antigens produce IL-13 that then acts on Gr-1 cells to induce TGF-β1; the latter then inhibits CD8+ T cells engaged in tumor immune surveillance; in effect, then, receptor signaling favors tumor growth. In addition to its signaling function and the induction of TGF-β1, IL-13Rα2 also influences IL-13Rα1 signaling in complex ways; thus, IL-13Rα2 emerges as a important component of IL-13 signaling, not only in its own right but also in its possible effect on its companion receptor.

Several associations have been described between the frequency of human leukocyte antigen (HLA) class I genes in certain populations and the risk of developing nasopharyngeal carcinoma (NPC). Associations between ethnic background and geographic distribution, and relative disease incidence have been reported. Populations in geographical areas at higher risk of developing NPC display HLA distribution patterns different and sometimes opposite from areas of low incidence, whereas populations in areas with intermediate incidence display a totally independent pattern. Two main reasons may explain this association between HLA phenotype distribution and the risk of developing NPC in various populations. First, given the fact that expression of Epstein-Barr Virus (EBV) proteins by cancer cells is tightly linked with NPC development, HLA may influence the development of NPC by modulating the expression of EBV proteins. This explanation is, however, based primarily on theoretical assumptions given that no clear definition of HLA binding pattern of EBV epitopes has been directly shown to significantly alter the recognition of EBV proteins and the risk of developing the disease. Alternatively, HLA may represent a genetic marker flagging the presence of a NPC predisposition locus in close linkage disequilibrium with the HLA class I region. A critical review of known HLA associations in various geographical areas and their interpretation will be presented in this review.

HPV has been linked to many human malignancies and, as such, represents a major public health crisis. The understanding of HPV biology, however, has helped tremendously in developing prophylactic vaccines, which should help in decreasing mortality due to HPV infections. Understanding HPV biology has allowed researchers to use the virus as a model for the development of not only prophylactic vaccines, but also therapeutic ones. The advantages of HPV as a model stem from the limited number of proteins encoded by the HPV genome that can be targeted by vaccines, and also from the restricted expression of certain viral proteins during different stages of infection. In this review, we discuss how HPV can be used as a model for the development of both prophylactic and therapeutic vaccines.