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19 pages, 4309 KiB

Open AccessArticle

mTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the Tumor Microenvironment

by Yu-Li Chen, Han-Wei Lin, Nai-Yun Sun, Jr-Chi Yie, Hsueh-Chih Hung, Chi-An Chen, Wei-Zen Sun and Wen-Fang Cheng

Cancers 2019, 11(5), 617; https://doi.org/10.3390/cancers11050617 - 02 May 2019

Cited by 12 | Viewed by 3123

Abstract

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to [...] Read more.

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8⁺ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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15 pages, 1639 KiB

Open AccessArticle

Cord-Blood-Stem-Cell-Derived Conventional Dendritic Cells Specifically Originate from CD115-Expressing Precursors

by Maud Plantinga, Colin G. de Haar, Ester Dünnebach, Denise A. M. H. van den Beemt, Kitty W. M. Bloemenkamp, Michal Mokry, Jaap Jan Boelens and Stefan Nierkens

Cancers 2019, 11(2), 181; https://doi.org/10.3390/cancers11020181 - 05 Feb 2019

Cited by 14 | Viewed by 3947

Abstract

Dendritic cells (DCs) are professional antigen-presenting cells which instruct both the innate and adaptive immune systems. Once mature, they have the capacity to activate and prime naïve T cells for recognition and eradication of pathogens and tumor cells. These characteristics make them excellent [...] Read more.

Dendritic cells (DCs) are professional antigen-presenting cells which instruct both the innate and adaptive immune systems. Once mature, they have the capacity to activate and prime naïve T cells for recognition and eradication of pathogens and tumor cells. These characteristics make them excellent candidates for vaccination strategies. Most DC vaccines have been generated from ex vivo culture of monocytes (mo). The use of mo-DCs as vaccines to induce adaptive immunity against cancer has resulted in clinical responses but, overall, treatment success is limited. The application of primary DCs or DCs generated from CD34⁺ stem cells have been suggested to improve clinical efficacy. Cord blood (CB) is a particularly rich source of CD34⁺ stem cells for the generation of DCs, but the dynamics and plasticity of the specific DC lineage development are poorly understood. Using flow sorting of DC progenitors from CB cultures and subsequent RNA sequencing, we found that CB-derived DCs (CB-DCs) exclusively originate from CD115⁺-expressing progenitors. Gene set enrichment analysis displayed an enriched conventional DC profile within the CD115-derived DCs compared with CB mo-DCs. Functional assays demonstrated that these DCs matured and migrated upon good manufacturing practice (GMP)-grade stimulation and possessed a high capacity to activate tumor-antigen-specific T cells. In this study, we developed a culture protocol to generate conventional DCs from CB-derived stem cells in sufficient numbers for vaccination strategies. The discovery of a committed DC precursor in CB-derived stem cell cultures further enables utilization of conventional DC-based vaccines to provide powerful antitumor activity and long-term memory immunity. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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Review

Jump to: Research

19 pages, 886 KiB

Open AccessReview

Dendritic Cell-Based and Other Vaccination Strategies for Pediatric Cancer

by Sévérine de Bruijn, Sébastien Anguille, Joris Verlooy, Evelien L. Smits, Viggo F. van Tendeloo, Maxime de Laere, Koenraad Norga, Zwi N. Berneman and Eva Lion

Cancers 2019, 11(9), 1396; https://doi.org/10.3390/cancers11091396 - 19 Sep 2019

Cited by 13 | Viewed by 4162

Abstract

Dendritic cell-based and other vaccination strategies that use the patient’s own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death [...] Read more.

Dendritic cell-based and other vaccination strategies that use the patient’s own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death among children past infancy in the Western world, the hope is that this form of active specific immunotherapy can play an important role in the pediatric population as well. Since children have more vigorous and adaptable immune systems than adults, therapeutic cancer vaccines are expected to have a better chance of creating protective immunity and preventing cancer recurrence in pediatric patients. Moreover, in contrast to conventional cancer treatments such as chemotherapy, therapeutic cancer vaccines are designed to specifically target tumor cells and not healthy cells or tissues. This reduces the likelihood of side effects, which is an important asset in this vulnerable patient population. In this review, we present an overview of the different therapeutic cancer vaccines that have been studied in the pediatric population, with a main focus on dendritic cell-based strategies. In addition, new approaches that are currently being investigated in clinical trials are discussed to provide guidance for further improvement and optimization of pediatric cancer vaccines. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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25 pages, 1046 KiB

Open AccessReview

Human Tumor-Infiltrating Dendritic Cells: From In Situ Visualization to High-Dimensional Analyses

by Margaux Hubert, Elisa Gobbini, Nathalie Bendriss-Vermare, Christophe Caux and Jenny Valladeau-Guilemond

Cancers 2019, 11(8), 1082; https://doi.org/10.3390/cancers11081082 - 30 Jul 2019

Cited by 28 | Viewed by 7628

Abstract

The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different [...] Read more.

The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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21 pages, 1865 KiB

Open AccessReview

Can Dendritic Cell Vaccination Prevent Leukemia Relapse?

by Liam J. O’Brien, Camille Guillerey and Kristen J. Radford

Cancers 2019, 11(6), 875; https://doi.org/10.3390/cancers11060875 - 22 Jun 2019

Cited by 12 | Viewed by 5806

Abstract

Leukemias are clonal proliferative disorders arising from immature leukocytes in the bone marrow. While the advent of targeted therapies has improved survival in certain subtypes, relapse after initial therapy is a major problem. Dendritic cell (DC) vaccination has the potential to induce tumor-specific [...] Read more.

Leukemias are clonal proliferative disorders arising from immature leukocytes in the bone marrow. While the advent of targeted therapies has improved survival in certain subtypes, relapse after initial therapy is a major problem. Dendritic cell (DC) vaccination has the potential to induce tumor-specific T cells providing long-lasting, anti-tumor immunity. This approach has demonstrated safety but limited clinical success until recently, as DC vaccination faces several barriers in both solid and hematological malignancies. Importantly, vaccine-mediated stimulation of protective immune responses is hindered by the aberrant production of immunosuppressive factors by cancer cells which impede both DC and T cell function. Leukemias present the additional challenge of severely disrupted hematopoiesis owing to both cytogenic defects in hematopoietic progenitors and an abnormal hematopoietic stem cell niche in the bone marrow; these factors accentuate systemic immunosuppression and DC malfunction. Despite these obstacles, several recent clinical trials have caused great excitement by extending survival in Acute Myeloid Leukemia (AML) patients through DC vaccination. Here, we review the phenotype and functional capacity of DCs in leukemia and approaches to harness DCs in leukemia patients. We describe the recent clinical successes in AML and detail the multiple new strategies that might enhance prognosis in AML and other leukemias. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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16 pages, 682 KiB

Open AccessReview

Unleashing Tumour-Dendritic Cells to Fight Cancer by Tackling Their Three A’s: Abundance, Activation and Antigen-Delivery

by Aleksandar Murgaski, Pauline M. R. Bardet, Sana M. Arnouk, Emile J. Clappaert and Damya Laoui

Cancers 2019, 11(5), 670; https://doi.org/10.3390/cancers11050670 - 14 May 2019

Cited by 14 | Viewed by 4402

Abstract

Recent advances in cancer immunotherapy have mainly focused on re-activating T-cell responses against cancer cells. However, both priming and activation of effector T-cell responses against cancer-specific antigens require cross-talk with dendritic cells (DCs), which are responsible for the capturing, processing and presentation of [...] Read more.

Recent advances in cancer immunotherapy have mainly focused on re-activating T-cell responses against cancer cells. However, both priming and activation of effector T-cell responses against cancer-specific antigens require cross-talk with dendritic cells (DCs), which are responsible for the capturing, processing and presentation of tumour-(neo)antigens to T cells. DCs consequently constitute an essential target in efforts to generate therapeutic immunity against cancer. This review will discuss recent research that is unlocking the cancer-fighting potential of tumour-infiltrating DCs. First, the complexity of DCs in the tumour microenvironment regarding the different subsets and the difficulty of translating mouse data into equivalent human data will be briefly touched upon. Mainly, possible solutions to problems currently faced in DC-based cancer treatments will be discussed, including their infiltration into tumours, activation strategies, and antigen delivery methods. In this way, we hope to put together a broad picture of potential synergistic therapies that could be implemented to harness the full capacity of tumour-infiltrating DCs to stimulate anti-tumour immune responses in patients. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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15 pages, 1245 KiB

Open AccessReview

Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses

by Philipp Schuster, Georg Lindner, Sabrina Thomann, Sebastian Haferkamp and Barbara Schmidt

Cancers 2019, 11(5), 651; https://doi.org/10.3390/cancers11050651 - 11 May 2019

Cited by 13 | Viewed by 5576

Abstract

The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as [...] Read more.

The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as long as these cells are unstimulated. Upon activation by synthetic Toll-like receptor agonists or viruses, however, pDC develop cytotoxic activities. Viruses have the additional advantage to augment cytotoxic activities of pDC via lytic replication in malignant lesions. These effects turn cold tumors into hotspots, recruiting further immune cells to the site of inflammation. Activated pDC contribute to cross-presentation of tumor-associated antigens by classical dendritic cells, which induce cytotoxic T-cells in particular in the presence of checkpoint inhibitors. The modification of oncolytic herpes viruses via genetic engineering favorably affects this process through the enhanced production of pro-inflammatory cytokines, curbing of tumor blood supply, and removal of extracellular barriers for efficient viral spread. Importantly, viral vectors may contribute to stimulation of memory-type adaptive immune responses through presentation of tumor-related neo- and/or self-antigens. Eventually, both replication-competent and replication-deficient herpes simplex virus 1 (HSV-1) may serve as vaccine vectors, which contribute to tumor regression by the stimulation of pDC and other dendritic cells in adjuvant and neo-adjuvant situations. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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16 pages, 4107 KiB

Open AccessReview

Blastic Plasmacytoid Dendritic Cell Neoplasm: State of the Art and Prospects

by Maria Rosaria Sapienza, Alessandro Pileri, Enrico Derenzini, Federica Melle, Giovanna Motta, Stefano Fiori, Angelica Calleri, Nicola Pimpinelli, Valentina Tabanelli and Stefano Pileri

Cancers 2019, 11(5), 595; https://doi.org/10.3390/cancers11050595 - 28 Apr 2019

Cited by 60 | Viewed by 8796

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare tumour, which usually affects elderly males and presents in the skin with frequent involvement of the bone-marrow, peripheral blood and lymph nodes. It has a dismal prognosis, with most patients dying within one [...] Read more.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare tumour, which usually affects elderly males and presents in the skin with frequent involvement of the bone-marrow, peripheral blood and lymph nodes. It has a dismal prognosis, with most patients dying within one year when treated by conventional chemotherapies. The diagnosis is challenging, since neoplastic cells can resemble lymphoblasts or small immunoblasts, and require the use of a large panel of antibodies, including those against CD4, CD56, CD123, CD303, TCL1, and TCF4. The morphologic and in part phenotypic ambiguity explains the uncertainties as to the histogenesis of the neoplasm that led to the use of various denominations. Recently, a series of molecular studies based on karyotyping, gene expression profiling, and next generation sequencing, have largely unveiled the pathobiology of the tumour and proposed the potentially beneficial use of new drugs. The latter include SL-401, anti-CD123 immunotherapies, venetoclax, BET-inhibitors, and demethylating agents. The epidemiologic, clinical, diagnostic, molecular, and therapeutic features of BPDCN are thoroughly revised in order to contribute to an up-to-date approach to this tumour that has remained an orphan disease for too long. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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33 pages, 1287 KiB

Open AccessFeature PaperReview

A Characterization of Dendritic Cells and Their Role in Immunotherapy in Glioblastoma: From Preclinical Studies to Clinical Trials

by Siddhartha Srivastava, Christina Jackson, Timothy Kim, John Choi and Michael Lim

Cancers 2019, 11(4), 537; https://doi.org/10.3390/cancers11040537 - 15 Apr 2019

Cited by 67 | Viewed by 12500

Abstract

Glioblastoma (GBM) is the most common and fatal primary central nervous system malignancy in adults with a median survival of less than 15 months. Surgery, radiation, and chemotherapy are the standard of care and provide modest benefits in survival, but tumor recurrence is [...] Read more.

Glioblastoma (GBM) is the most common and fatal primary central nervous system malignancy in adults with a median survival of less than 15 months. Surgery, radiation, and chemotherapy are the standard of care and provide modest benefits in survival, but tumor recurrence is inevitable. The poor prognosis of GBM has made the development of novel therapies targeting GBM of paramount importance. Immunotherapy via dendritic cells (DCs) has garnered attention and research as a potential strategy to boost anti-tumor immunity in recent years. As the “professional” antigen processing and presenting cells, DCs play a key role in the initiation of anti-tumor immune responses. Pre-clinical studies in GBM have shown long-term tumor survival and immunological memory in murine models with stimulation of DC activity with various antigens and costimulatory molecules. Phase I and II clinical trials of DC vaccines in GBM have demonstrated some efficacy in improving the median overall survival with minimal to no toxicity with promising initial results from the first Phase III trial. However, there remains no standardization of vaccines in terms of which antigens are used to pulse DCs ex vivo, sites of DC injection, and optimal adjuvant therapies. Future work with DC vaccines aims to elucidate the efficacy of DC-based therapy alone or in combination with other immunotherapy adjuvants in additional Phase III trials. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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21 pages, 3175 KiB

Open AccessEditor’s ChoiceReview

Dendritic Cells and Cancer: From Biology to Therapeutic Intervention

by Ben Wylie, Christophe Macri, Justine D. Mintern and Jason Waithman

Cancers 2019, 11(4), 521; https://doi.org/10.3390/cancers11040521 - 11 Apr 2019

Cited by 95 | Viewed by 8561

Abstract

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are [...] Read more.

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are often diminished, or suppressed, by factors encountered in the tumor microenvironment. Furthermore, DC populations with immunosuppressive activities are also recruited to tumors, limiting T cell infiltration and promoting tumor growth. Anti-cancer therapies can impact the function of tumor-associated DC and/or alter their phenotype. Therefore, the design of effective anti-cancer therapies for clinical translation should consider how best to boost tumor-associated DC function to drive anti-tumor immunity. In this review, we discuss the different subsets of tumor-infiltrating DC and their role in anti-tumor immunity. Moreover, we describe strategies to enhance DC function within tumors and harness these cells for effective tumor immunotherapy. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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14 pages, 707 KiB

Open AccessReview

Immunology of Plasmacytoid Dendritic Cells in Solid Tumors: A Brief Review

by Vladimír Koucký, Jan Bouček and Anna Fialová

Cancers 2019, 11(4), 470; https://doi.org/10.3390/cancers11040470 - 03 Apr 2019

Cited by 48 | Viewed by 5884

Abstract

The immune response, both innate and adaptive, is a key player in cancer development and progression. Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that play one of the central roles in the immune system. They are known mostly as the [...] Read more.

The immune response, both innate and adaptive, is a key player in cancer development and progression. Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells that play one of the central roles in the immune system. They are known mostly as the major IFN type I-producing cells upon stimulation of Toll-like receptors 7 and 9. However, based on current knowledge, the functionality of pDCs is very complex, as they have the ability to affect many other cell types. In the context of the tumor tissue, pDCs were mostly described to show substantial functional defects and therefore contribute to the establishement of immunosuppressive tumor microenvironment. Immunotherapeutic approaches have proven to be one of the most promising treatment strategies in the last decade. In view of this fact, it is crucial to map the complexity of the tumor microenvironment in detail, including less numerous cell types. This review focuses on pDCs in relation to solid tumors. We provide a summary of current data on the role of pDCs in different tumor types and suggest their possible clinical applications. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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17 pages, 1058 KiB

Open AccessReview

Use of Dendritic Cell Receptors as Targets for Enhancing Anti-Cancer Immune Responses

by Md Kamal Hossain and Katherine A. Wall

Cancers 2019, 11(3), 418; https://doi.org/10.3390/cancers11030418 - 24 Mar 2019

Cited by 67 | Viewed by 7721

Abstract

A successful anti-cancer vaccine construct depends on its ability to induce humoral and cellular immunity against a specific antigen. Targeting receptors of dendritic cells to promote the loading of cancer antigen through an antibody-mediated antigen uptake mechanism is a promising strategy in cancer [...] Read more.

A successful anti-cancer vaccine construct depends on its ability to induce humoral and cellular immunity against a specific antigen. Targeting receptors of dendritic cells to promote the loading of cancer antigen through an antibody-mediated antigen uptake mechanism is a promising strategy in cancer immunotherapy. Researchers have been targeting different dendritic cell receptors such as Fc receptors (FcR), various C-type lectin-like receptors such as dendritic and thymic epithelial cell-205 (DEC-205), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), and Dectin-1 to enhance the uptake process and subsequent presentation of antigen to T cells through major histocompatibility complex (MHC) molecules. In this review, we compare different subtypes of dendritic cells, current knowledge on some important receptors of dendritic cells, and recent articles on targeting those receptors for anti-cancer immune responses in mouse models. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

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