Therapeutic Implications of Immunogenic Cell Death in Human Cancer (original) (raw)

Dendritic cells and tumor immunity

Seminars in Immunology, 2001

Researchers and clinicians have tried for decades to use the mechanisms of immunity for the fight against cancer. Early attempts aimed at the instrumentation of soluble immune mediators such as antibodies or cytotoxic proteins for the therapy of malignancies. Major improvements in understanding the induction and regulation of cellular immunity have now made it possible to generate effector cells in cancer patients which are specific for the neoplastic disease. At the beginning of every cellular immune reaction against cancers tumor antigens have to be presented to T cells in order to activate them and drive them into clonal expansion. This is done by antigen presenting cells, the most powerful of which is the dendritic cell (DC). While DC were hard to isolate initially, they can be generated in large numbers in vitro today and manipulated in multiple ways before given back to a patient to induce tumor immunity. Thus, a great amount of hope lies in the use of DC as inducers of tumor immunity. However, the first clinical studies, which have now been completed with only limited success make clear, that still a lot of open questions remain to be answered. This review tries to give an overview of this rapidly developing field, mentioning the major conceptual approaches and techniques, but also discussing important caveats. The next years will show whether we can improve our understanding of DC biology and the mechanisms of immune induction strongly enough to effectively employ DC for immunotherapy of cancer.

Dendritic cells in cancer immunology and immunotherapy

Nature Reviews Immunology, 2019

Cancers originate from the uncontrolled proliferative activity of the organism's cells and present characteristic hallmarks 1. Despite their self-origin, tumours can induce immune responses. However, the incomplete elimination of tumour cells by the immune system can result in the persistence of 'immune-edited' tumours that are not efficiently cleared by the immune system 2. The association of infections with spontaneous tumour regression and the capacity of the immune system to reject immunogenic tumours in preclinical models 1 support the role of the immune system in protection against cancers. Moreover, large-scale projects such as The Cancer Genome Atlas and the Immunoprofiler Initiative have identified tumour-infiltrating immune cells-either through gene-expression signatures 3-6 or by direct observation of these cell types 7-as important correlates of cancer prognosis and treatment responsiveness. Although dendritic cells (DCs) constitute a rare immune cell population within tumours and lymphoid organs, these cells are central for the initiation of antigen-specific immunity and tolerance 8. Therefore, manipulation of DCs holds great potential for inducing efficient antitumour immunity 8. DCs promote immunity or tolerance by sampling and presenting antigens to T cells and by providing immunomodulatory signals through cell-cell contacts and cytokines 9,10. DC functions are determined by their integration of environmental signals, which are sensed via surfaceexpressed and intracellular receptors for cytokines, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) 11. Recent data highlight the specific roles of DC subsets in antitumour immunity, with key implications for therapy 12,13. In that regard, most of our general understanding of DC subsets and functions is based on observations in mouse models, and, currently, increasing efforts aim to evaluate the biology of human DCs. In this Review, we will discuss the main functions of DCs in cancer immunology and consider the therapeutic potential of targeting DCs in patients with cancer.

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

Pharmaceutics

The safety and feasibility of dendritic cell (DC)-based immunotherapies in cancer management have been well documented after more than twenty-five years of experimentation, and, by now, undeniably accepted. On the other hand, it is equally evident that DC-based vaccination as monotherapy did not achieve the clinical benefits that were predicted in a number of promising preclinical studies. The current availability of several immune modulatory and targeting approaches opens the way to many potential therapeutic combinations. In particular, the evidence that the immune-related effects that are elicited by immunogenic cell death (ICD)-inducing therapies are strictly associated with DC engagement and activation strongly support the combination of ICD-inducing and DC-based immunotherapies. In this review, we examine the data in recent studies employing tumor cells, killed through ICD induction, in the formulation of anticancer DC-based vaccines. In addition, we discuss the opportunity to...

Dendritic cells and cytokines in immune rejection of cancer

Cytokine & Growth Factor Reviews, 2008

Dendritic cells (DCs) play a crucial role in linking innate and adaptive immunity and, thus, in the generation of a protective immune response against both infectious diseases and tumors. The ability of DCs to prime and expand an immune response is regulated by signals acting through soluble mediators, mainly cytokines and chemokines. Understanding how cytokines influence DC functions and orchestrate the interactions of DCs with other immune cells is strictly instrumental to the progress in cancer immunotherapy. Herein, we will illustrate how certain cytokines and immune stimulating molecules can induce and sustain the antitumor immune response by acting on DCs. We will also discuss these cytokine-DC interactions in the light of clinical results in cancer patients. #

Dendritic Cells and their Receptors in Antitumor Immune Response

Current Molecular Medicine, 2009

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.

Tumor's other immune targets: dendritic cells

Journal of …, 1999

The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time-and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumorinduced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumorassociated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases. J. Leukoc. Biol. 66: 336-344; 1999.

Cellular Immunotherapy with Dendritic Cells in Cancer: Current Status

Stem Cells, 2004

The first demonstration that tumor rejection antigens exist goes back to the late 1980s when tumor-infiltrating lymphocytes from melanoma patients were shown to lyse HLAmatched melanoma cell lines, suggesting the existence of shared melanoma antigens [1]. In the subsequent years, the first genes encoding tumor antigens (such as tyrosinase, gp-100, the MART and MAGE genes) were cloned, and the immunogenic epitopes were identified. These and subsequent studies pointed out that tumors often upregulate the expression of molecules that are normally suppressed or expressed at much lower levels in adult tissues. T lymphocytes capable of recognizing these antigens usually exist in the periphery, possibly due to the lack of presentation of these antigens during thymic selection or lower avidity of the T-cell receptor (TCR) . However, in most cases, the immune system fails to recognize and destroy tumor cells that may give rise to clinically relevant malignancies. The tumor escape mechanisms include the inefficiency of tumor cells as antigen-presenting cells (APCs) and the lack of efficient contact between immune system and tumor cells .

Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies

Expert Review of Vaccines, 2013

Dendritic cells (DCs) are specialized immunostimulatory cells involved in the induction and regulation of immune responses. The feasibility of large-scale ex vivo generation of DCs from patients' monocytes allows for therapeutic application of ex vivo-cultured DCs to bypass the dysfunction of endogenous DCs, restore immune surveillance, induce cancer regression or stabilization or delay or prevent its recurrence. While the most common paradigm of the therapeutic application of DCs reflects their use as cancer 'vaccines', additional and potentially more effective possibilities include the use of patients' autologous DCs as parts of more comprehensive therapies involving in vivo or ex vivo induction of tumor-reactive T cells and the measures to counteract systemic and local immunosuppression in tumor-bearing hosts. Ex vivocultured DCs can be instructed to acquire distinct functions relevant for the induction of effective cancer immunity (DC polarization), such as the induction of different effector functions or different homing properties of tumor-specific T cells (delivery of 'signal 3' and 'signal 4'). These considerations highlight the importance of the application of optimized conditions for the ex vivo culture of DCs and the potential combination of DC therapies with additional immune interventions to facilitate the entry of DC-induced T cells to tumor tissues and their local antitumor functions.