Dendritic Cells and Cancer Immunotherapy: The Adjuvant Effect

Dendritic cells (DCs) are immune specialized cells playing a critical role in promoting immune response against antigens, and may represent important targets for therapeutic interventions in cancer. DCs can be stimulated ex vivo with pro-inflammatory molecules and loaded with tumor-specific antigen(s). Protocols describing the specific details of DCs vaccination manufacturing vary widely, but regardless of the employed protocol, the DCs vaccination safety and its ability to induce antitumor responses is clearly established. Many years of studies have focused on the ability of DCs to provide overall survival benefits at least for a selection of cancer patients. Lessons learned from early trials lead to the hypothesis that, to improve the efficacy of DCs-based immunotherapy, this should be combined with other treatments. Thus, the vaccine's ultimate role may lie in the combinatorial approaches of DCs-based immunotherapy with chemotherapy and radiotherapy, more than in monotherapy. In this review, we address some key questions regarding the integration of DCs vaccination with multimodality therapy approaches for cancer treatment paradigms.

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CYP450-derived oxylipins mediate inflammatory resolution

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521453113 ◽

2016 ◽

Vol 113 (23) ◽

pp. E3240-E3249 ◽

Cited By ~ 56

Author(s):

Derek W. Gilroy ◽

Matthew L. Edin ◽

Roel P. H. De Maeyer ◽

Jonas Bystrom ◽

Justine Newson ◽

...

Keyword(s):

Dendritic Cells ◽

Adaptive Immunity ◽

Ex Vivo ◽

Critical Role ◽

Regulatory System ◽

Mononuclear Phagocyte ◽

Innate And Adaptive Immunity ◽

Wound Debridement ◽

Opposing Effects

Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24–48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid- and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1+, Ly6chi, CCR2hi, CCL2hi, and CX3CR1lo. In addition, expression of F4/80 and the recruitment of T cells, B cells, and dendritic cells were suppressed. sEH (Ephx2)−/− mice, which have elevated epoxy-oxylipins, demonstrated opposing effects to epoxI-treated mice: reduced Ly6chi monocytes and elevated F4/80hi macrophages and B, T, and dendritic cells. Ly6chi and Ly6clo monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.

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Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha

BMC Immunology ◽

10.1186/1471-2172-9-32 ◽

2008 ◽

Vol 9 (1) ◽

pp. 32 ◽

Cited By ~ 4

Author(s):

Sukchai Satthaporn ◽

Mark M Aloysius ◽

Richard A Robins ◽

Chandan Verma ◽

Suebwong Chuthapisith ◽

...

Keyword(s):

Breast Cancer ◽

Dendritic Cells ◽

Ex Vivo ◽

Critical Role ◽

Operable Breast Cancer ◽

Ifn Alpha

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Primary Human Dendritic Cells and Whole-Blood based Assays to Evaluate Immuno-Modulatory Properties of Heat-Killed Commensal Bacteria

Vaccines ◽

10.3390/vaccines9030225 ◽

2021 ◽

Vol 9 (3) ◽

pp. 225

Author(s):

James E. Norton Norton, Jr. ◽

Sushma Kommineni ◽

Patricia Akrivoulis ◽

Dario A. Gutierrez ◽

Daria J. Hazuda ◽

...

Keyword(s):

Dendritic Cells ◽

Whole Blood ◽

Culture System ◽

Immune Cell ◽

Ex Vivo ◽

Critical Role ◽

Commensal Bacteria ◽

Host Immune System ◽

Bacterial Strains

There is mounting evidence that the microbiome plays a critical role in training and maturation of the host immune system. Pre-clinical and clinical studies have shown that microbiome perturbation is correlated with sub-optimal host responses to vaccines and cancer immunotherapy. As such, identifying species of commensal bacteria capable of modulating immunological outcomes is of considerable interest. Currently, the lack of reliable primary immune cell-based assays capable of differentiating immuno-modulatory properties of various commensal bacteria is a major limitation. Here, we demonstrate that primary human monocyte-derived dendritic cells (MoDC) are capable of stratifying different strains of live and heat-killed commensal bacteria in an in vitro culture system. Specifically, heat-killed bacterial strains were able to differentially modulate co-stimulation/maturation markers CD80, CD83, and HLA-DR, as well as cytokine/chemokine signatures, such as IL-1b, MIP-1a, and TNFa in primary human MoDC. We further validated our observations using the TruCulture® (Myriad RBM, Inc., Austin, TX, USA) whole-blood ex vivo culture system. Using this ex vivo system allowed us to measure immune-altering effects of commensal bacteria in primary human whole-blood. As such, we report that both these primary in vitro and ex vivo systems are robust and enable identification, stratification, and differentiation of various commensal bacteria as potential modulators of host immunity.

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Dendritic Cells in Anticancer Vaccination: Rationale for Ex Vivo Loading or In Vivo Targeting

Cancers ◽

10.3390/cancers12030590 ◽

2020 ◽

Vol 12 (3) ◽

pp. 590 ◽

Cited By ~ 8

Author(s):

Alexey V. Baldin ◽

Lyudmila V. Savvateeva ◽

Alexandr V. Bazhin ◽

Andrey A. Zamyatnin

Keyword(s):

Dendritic Cells ◽

Checkpoint Inhibitors ◽

Ex Vivo ◽

Combination Immunotherapy ◽

Efficacy And Safety ◽

Administration Routes ◽

Dc Vaccine ◽

Dc Vaccines ◽

Selection Of

Dendritic cells (DCs) have shown great potential as a component or target in the landscape of cancer immunotherapy. Different in vivo and ex vivo strategies of DC vaccine generation with different outcomes have been proposed. Numerous clinical trials have demonstrated their efficacy and safety in cancer patients. However, there is no consensus regarding which DC-based vaccine generation method is preferable. A problem of result comparison between trials in which different DC-loading or -targeting approaches have been applied remains. The employment of different DC generation and maturation methods, antigens and administration routes from trial to trial also limits the objective comparison of DC vaccines. In the present review, we discuss different methods of DC vaccine generation. We conclude that standardized trial designs, treatment settings and outcome assessment criteria will help to determine which DC vaccine generation approach should be applied in certain cancer cases. This will result in a reduction in alternatives in the selection of preferable DC-based vaccine tactics in patient. Moreover, it has become clear that the application of a DC vaccine alone is not sufficient and combination immunotherapy with recent advances, such as immune checkpoint inhibitors, should be employed to achieve a better clinical response and outcome.

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Cell-based cancer gene therapy: breaking tolerance or inducing autoimmunity?

Animal Health Research Reviews ◽

10.1079/ahr200473 ◽

2004 ◽

Vol 5 (2) ◽

pp. 227-234 ◽

Cited By ~ 13

Author(s):

Juan Carlos Rodriguez-Lecompte ◽

Steve Kruth ◽

Steve Gyorffy ◽

Yong-Hong Wan ◽

Jack Gauldie

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Tumor Immunity ◽

Ex Vivo ◽

Critical Role ◽

Tumor Vaccines ◽

Strong Immune Response ◽

Tumor Associated Antigens ◽

Tumor Types

AbstractThis review examines the mechanisms involved in anti-tumor immunity and how peptides present in many tumor types (tumor-associated antigens) are recognized by T cells from tumor-bearing cancer patients. Tumor-associated antigens are derived from proteins that are also expressed in normal cells. It is predicted that immune responses to such peptides will be compromised by self-tolerance or that stimulation of effective immune responses will be accompanied by autoimmunity. We also consider that the immunity induced against two autoantigens, which are highly conserved in vertebrates, involve qualitatively different mechanisms, such as the production of antibodies and cell-mediated immune responses. However, both pathways lead to tumor immunity and identical phenotypic manifestations of autoimmunity. Appropriate selection of the optimal tumor antigen is critical for the induction of an anti-tumor immune response. Thus, we stress that the methods for antigen presentation using dendritic cells play a critical role in the development of tumor vaccines, to break immune tolerance and induce a strong immune response against them. The viability and feasibility of expansion of canine dendritic cells from bone marrow and peripheral blood ex vivo for the treatment of spontaneous cancers in dogs is also discussed.

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Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

Clinical Science ◽

10.1042/cs20190999 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2283-2299

Author(s):

Apabrita Ayan Das ◽

Devasmita Chakravarty ◽

Debmalya Bhunia ◽

Surajit Ghosh ◽

Prakash C. Mandal ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Chronic Inflammation ◽

Ex Vivo ◽

Human Subjects ◽

Critical Role ◽

Atherosclerotic Cardiovascular Disease ◽

Tnf Α ◽

Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

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