CD4 and CD8 T lymphocyte interplay in controlling tumor growth

The outstanding clinical success of immune checkpoint blockade has revived the interest in underlying mechanisms of the immune system that are capable of eliminating tumors even in advanced stages. In this scenario, CD4 and CD8 T cell responses are part of the cancer immune cycle and both populations significantly influence the clinical outcome. In general, the immune system has evolved several mechanisms to protect the host against cancer. Each of them has to be undermined or evaded during cancer development to enable tumor outgrowth. In this review, we give an overview of T lymphocyte-driven control of tumor growth and discuss the involved tumor-suppressive mechanisms of the immune system, such as senescence surveillance, cancer immunosurveillance, and cancer immunoediting with respect to recent clinical developments of immunotherapies. The main focus is on the currently existing knowledge about the CD4 and CD8 T lymphocyte interplay that mediates the control of tumor growth.     

Mechanistic insights into the efficacy of cell penetrating peptide-based cancer vaccines

Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient’s immune system against tumor-derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies.     

What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.Received 19 July 2002; received after revision 11 December 2002; accepted 13 December 2002     

In vivo imaging of therapy-induced anti-cancer immune responses in humans

Immunotherapy aims to re-engage and revitalize the immune system in the fight against cancer. Research over the past decades has shown that the relationship between the immune system and human cancer is complex, highly dynamic, and variable between individuals. Considering the complexity, enormous effort and costs involved in optimizing immunotherapeutic approaches, clinically applicable tools to monitor therapy-induced immune responses in vivo are most warranted. However, the development of such tools is complicated by the fact that a developing immune response encompasses several body compartments, e.g., peripheral tissues, lymph nodes, lymphatic and vascular systems, as well as the tumor site itself. Moreover, the cells that comprise the immune system are not static but constantly circulate through the vascular and lymphatic system. Molecular imaging is considered the favorite candidate to fulfill this task. The progress in imaging technologies and modalities has provided a versatile toolbox to address these issues. This review focuses on the detection of therapy-induced anticancer immune responses in vivo and provides a comprehensive overview of clinically available imaging techniques as well as perspectives on future developments. In the discussion, we will focus on issues that specifically relate to imaging of the immune system and we will discuss the strengths and limitations of the current clinical imaging techniques. The last section provides future directions that we envision to be crucial for further development.     

Positive and negative influence of the matrix architecture on antitumor immune surveillance

The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells.     

Towards progress on DNA vaccines for cancer

Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response while also targeting tumor evasion mechanisms. Received 2 April 2007; received after revision 14 May 2007; accepted 21 May 2007     

Formation and role of exosomes in cancer

Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer.     

Role of microRNAs in malignant mesothelioma

Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly severe, with a median survival of approximately 9–12 months and latency between exposure and diagnosis ranging from 20–50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17–22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.     

Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.     

Intestinal epithelial barrier and mucosal immunity

Intestinal mucosa integrates primary digestive functions with immune functions such as pathogen surveillance, antigen transport and induction of mucosal immunity and tolerance. Intestinal adaptive immunity is elicited in organized mucosa-associated lymphoid tissue (O-MALT) that is composed of antigen-presenting cells and lymphocytes and achieved by effector cells widely distributed in mucosa (diffuse MALT or D-MALT). Interaction between the intestinal epithelium, the O-MALT and the diffuse MALT plays a critical role in establishing an adequate immune response. In regions associated to O-MALT, lympho-epithelial cross-talks lead to acquisition of a specific epithelial phenotype that contributes to O-MALT organization and functionality. Beyond the expression of several innate immune functions, the intestinal epithelium may directly take up and present antigens due to the expression of major histocompatibility complex (MHC) and MHC-related molecules. A complex genetic program that will be outlined in the present review controls the development of immune functions of the intestinal epithelium. The effect of environmental signals on the modulation of this ontogenetic program during development and neonatal life, from bioactive components of amniotic fluid to lactation and bacterial colonization, will be discussed.     

The pleiotropic roles of ADAM9 in the biology of solid tumors

A disintegrin and a metalloprotease (ADAM) 9 is a metzincin cell-surface protease involved in several biological processes such as myogenesis, fertilization, cell migration, inflammatory response, proliferation, and cell–cell interactions. ADAM9 has been found over-expressed in several solid tumors entities such as glioma, melanoma, prostate cancer, pancreatic ductal adenocarcinoma, gastric, breast, lung, and liver cancers. Immunohistochemical analyses highlight ADAM9 expression by actual cancer cells and associate its abundant presence with clinicopathological features such as shortened overall survival, poor tumor grade, de-differentiation, therapy resistance, and metastasis formation. In each of these tumors, ADAM9 may contribute to tumor biology via proteolytic or non-proteolytic mechanisms. For example, in liver cancer, ADAM9 has been found to shed MHC class I polypeptide-related sequence A, contributing towards the evasion of tumor immunity. ADAM9 may also contribute to tumor biology in non-proteolytic ways probably through interaction with different integrins. For example, in melanoma, the interaction between ADAM9 and β1 integrins facilitates tumor stroma cross talks, which then promotes invasion and metastasis via the activation of MMP1 and MMP2. In breast cancer, the interaction between β1 integrins on endothelial cells and ADAM9 on tumor cells facilitate tumor cell extravasation and invasion to distant sites. This review summarizes the present knowledge on ADAM9 in solid cancers, and the different mechanisms which it employ to drive tumor progression.     

The battle against immunopathology: infectious tolerance mediated by regulatory T cells

Infectious tolerance is a process whereby one regulatory lymphoid population confers suppressive capacity on another. Diverse immune responses are induced following infection or inflammatory insult that can protect the host, or potentially cause damage if not properly controlled. Thus, the process of infectious tolerance may be critical in vivo for exerting effective immune control and maintaining immune homeostasis by generating specialized regulatory sub-populations with distinct mechanistic capabilities. Foxp3(+) regulatory T cells (T(regs)) are a central mediator of infectious tolerance through their ability to convert conventional T cells into induced regulatory T cells (iT(regs)) directly by secretion of the suppressive cytokines TGF-β, IL-10, or IL-35, or indirectly via dendritic cells. In this review, we will discuss the mechanisms and cell populations that mediate and contribute to infectious tolerance, with a focus on the intestinal environment, where tolerance induction to foreign material is critical.     

Immunogenicity of necrotic cell death

The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity.     

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process. Received 4 July 2005; received after revision 3 November 2005; accepted 14 November 2005     

Inhibitors of protein translocation across membranes of the secretory pathway: novel antimicrobial and anticancer agents

Proteins routed to the secretory pathway start their journey by being transported across biological membranes, such as the endoplasmic reticulum. The essential nature of this protein translocation process has led to the evolution of several factors that specifically target the translocon and block translocation. In this review, various translocation pathways are discussed together with known inhibitors of translocation. Properties of signal peptide-specific systems are highlighted for the development of new therapeutic and antimicrobial applications, as compounds can target signal peptides from either host cells or pathogens and thereby selectively prevent translocation of those specific proteins. Broad inhibition of translocation is also an interesting target for the development of new anticancer drugs because cancer cells heavily depend on efficient protein translocation into the endoplasmic reticulum to support their fast growth.     

RANKL,RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases

1997 saw the identification of a novel set of proteins within the tumor necrosis factor (TNF)/TNF receptor families that are required for the control of bone remodeling. Therefore, these receptors, receptor activator of nuclear factor kappa B (RANK), osteoprotegerin (OPG) and their ligand RANK ligand (RANKL) became the critical molecular triad controlling osteoclastogenesis and pathophysiologic bone remodeling. However, the establishment of the corresponding knock-out and transgenic mice revealed unexpected results, most particularly, the involvement of these factors in the vascular system and immunity. Thus, the OPG/RANK/RANKL molecular triad appears to be associated with vascular calcifications and plays a pivotal function in the development of the immune system through dendritic cells. OPG/RANK/RANKL thus constitute a molecular bridge spanning bone metabolism, vascular biology and immunity. This review summarizes recent knowledge of OPG/RANK/RANKL interactions and activities as well as the current evidence for their participation in osteoimmunology and vascular diseases. In fine, the targeting of the OPG/RANK/RANKL axis as novel therapeutic approaches will be discussed. Received 27 February 2007; accepted 4 April 2007     

Combining immune cell and viral therapy for the treatment of cancer

A variety of viral-based and immune cell therapies have been proposed for use in the treatment of cancer. One possible approach to improve the effectiveness of these biological agents may be to combine them such that we can take advantage of natural immune cell-pathogen relationships. Here we discuss these potential approaches with particular emphasis on the use of immune cells as carrier vehicles to deliver viral therapies to the tumor. Received 15 December 2006; received after revision 28 January 2007; accepted 5 March 2007     

Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals

Natural killer (NK) cells have originally been identified by their spontaneous cytolytic potential against tumor cells, which, however, might result from pre-activation due to prior pathogen exposure. Resting NK cells, on the contrary, require activation by bystander antigen-presenting cells to reach their full functional competence. In this review, we will summarize studies on how dendritic cells (DCs), the most potent type of antigen-presenting cell, communicate with human NK cells to activate them in secondary lymphoid organs and to integrate signals from activated NK cells at sites of inflammation for their own maturation. Furthermore, we will review aspects of the immunological synapse, which mediates this cross-talk. These studies provide the mechanistic understanding of how mature DCs can activate NK cells and survive to go on for the activation of adaptive immunity. This feature of DCs, to activate different waves of immune responses, could be harnessed for immunotherapies, including vaccinations.