-
Biology Direct Nov 2023Cancer immunotherapy, alone or in combination with conventional therapies, has revolutionized the landscape of antineoplastic treatments, with dendritic cells (DC)... (Review)
Review
Cancer immunotherapy, alone or in combination with conventional therapies, has revolutionized the landscape of antineoplastic treatments, with dendritic cells (DC) emerging as key orchestrators of anti-tumor immune responses. Among the distinct DC subsets, conventional type 1 dendritic cells (cDC1) have gained prominence due to their unique ability to cross-present antigens and activate cytotoxic T lymphocytes. This review summarizes the distinctive characteristics of cDC1, their pivotal role in anticancer immunity, and the potential applications of cDC1-based strategies in immunotherapy.
Topics: Humans; Dendritic Cells; Neoplasms; Immunotherapy; CD8-Positive T-Lymphocytes
PubMed: 37907944
DOI: 10.1186/s13062-023-00430-5 -
Cell Death & Disease Jul 2023The cytokine tumor necrosis factor (TNF) critically regulates the intertwined cell death and pro-inflammatory signaling pathways of dendritic cells (DCs) via ubiquitin...
The cytokine tumor necrosis factor (TNF) critically regulates the intertwined cell death and pro-inflammatory signaling pathways of dendritic cells (DCs) via ubiquitin modification of central effector molecules, but the intrinsic molecular switches deciding on either pathway are incompletely defined. Here, we uncover that the ovarian tumor deubiquitinating enzyme 7b (OTUD7b) prevents TNF-induced apoptosis of DCs in infection, resulting in efficient priming of pathogen-specific CD8 T cells. Mechanistically, OTUD7b stabilizes the E3 ligase TNF-receptor-associated factor 2 (TRAF2) in human and murine DCs by counteracting its K48-ubiquitination and proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, which mediates activation of NF-κB and MAP kinases, IL-12 production, and expression of anti-apoptotic cFLIP and Bcl-xL. We show that mice with DC-specific OTUD7b-deficiency displayed DC apoptosis and a failure to induce CD8 T cell-mediated brain pathology, experimental cerebral malaria, in a murine malaria infection model. Together, our data identify the deubiquitinating enzyme OTUD7b as a central molecular switch deciding on survival of human and murine DCs and provides a rationale to manipulate DC responses by targeting their ubiquitin network downstream of the TNF receptor pathway.
Topics: Animals; Humans; Mice; Apoptosis; CD8-Positive T-Lymphocytes; Dendritic Cells; Deubiquitinating Enzymes; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases; Ubiquitins
PubMed: 37516734
DOI: 10.1038/s41419-023-06014-5 -
Haematologica Jan 2024Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that presents with characteristic dark purple skin papules, plaques, and tumors,... (Review)
Review
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that presents with characteristic dark purple skin papules, plaques, and tumors, but may also involve the bone marrow, blood, lymph nodes, and central nervous system. The disease, which commonly affects older men but can also present in children, is associated with a distinct immunophenotype including universal expression of CD123, the α chain of the interleukin 3 receptor. Recently, tagraxofusp, a CD123-targeting drug consisting of the ligand for CD123, interleukin 3, conjugated to a truncated diphtheria toxin payload was approved for treatment of BPDCN. This was the first agent specifically approved for BPDCN and the first CD123 targeted agent in oncology. Here, we review the development of tagraxofusp, and the key preclinical insights and clinical data that led to approval. Tagraxofusp treatment is associated with a unique toxicity, capillary leak syndrome (CLS), which can be severe but is manageable with proper patient selection and monitoring, early recognition, and directed intervention. We outline our approach to the use of tagraxofusp and discuss open questions in the treatment of BPDCN. Overall, tagraxofusp represents a unique targeted therapy and a step forward in meeting an unmet need for patients with this rare disease.
Topics: Male; Child; Humans; Aged; Interleukin-3 Receptor alpha Subunit; Dendritic Cells; Hematologic Neoplasms; Recombinant Fusion Proteins; Acute Disease; Myeloproliferative Disorders; Skin Neoplasms
PubMed: 36951152
DOI: 10.3324/haematol.2022.282171 -
International Journal of Molecular... Feb 2024Atherosclerosis, a major contributor to cardiovascular morbidity and mortality, is characterized by chronic inflammation of the arterial wall. This inflammatory process... (Review)
Review
Atherosclerosis, a major contributor to cardiovascular morbidity and mortality, is characterized by chronic inflammation of the arterial wall. This inflammatory process is initiated and maintained by both innate and adaptive immunity. Dendritic cells (DCs), which are antigen-presenting cells, play a crucial role in the development of atherosclerosis and consist of various subtypes with distinct functional abilities. Following the recognition and binding of antigens, DCs become potent activators of cellular responses, bridging the innate and adaptive immune systems. The modulation of specific DC subpopulations can have either pro-atherogenic or atheroprotective effects, highlighting the dual pro-inflammatory or tolerogenic roles of DCs. In this work, we provide a comprehensive overview of the evolving roles of DCs and their subtypes in the promotion or limitation of atherosclerosis development. Additionally, we explore antigen pulsing and pharmacological approaches to modulate the function of DCs in the context of atherosclerosis.
Topics: Humans; Dendritic Cells; Atherosclerosis; Adaptive Immunity; Inflammation
PubMed: 38397127
DOI: 10.3390/ijms25042450 -
Journal For Immunotherapy of Cancer Dec 2023Natural killer (NK) cells are innate lymphocytes with a key role in the defense against tumors. Recently, allogeneic NK cell-based therapies have gained interest because...
Allogeneic NK cells induce monocyte-to-dendritic cell conversion, control tumor growth, and trigger a pro-inflammatory shift in patient-derived cultures of primary and metastatic colorectal cancer.
INTRODUCTION
Natural killer (NK) cells are innate lymphocytes with a key role in the defense against tumors. Recently, allogeneic NK cell-based therapies have gained interest because of their ability to directly lyse tumor cells without inducing graft-versus-host disease. As NK cells are also able to influence the function of other immune cells (most notably dendritic cells (DC)), a better understanding of the effects of allogeneic NK cell products on the host immune system is required. In this study, we analyzed the effects of an allogeneic off-the-shelf NK cell product, on the tumor microenvironment (TME) of primary and metastatic colorectal cancer (pCRC and mCRC, respectively). Moreover, we explored if the combination of NK cells with R848, a toll-like receptors 7/8 ligand, could further enhance any pro-inflammatory effects.
METHODS
Ex vivo expanded umbilical cord blood stem cell derived NK cells were co-cultured with pCRC or mCRC single-cell suspensions in the presence or absence of R848 for 5 days, during and after which flow cytometry and cytokine release profiling were performed.
RESULTS
NK cells efficiently induced lysis of tumor cells in both pCRC and mCRC single-cell suspensions and thereby controlled growth rates during culture. They also induced differentiation of infiltrating monocytic cells to an activated DC phenotype. Importantly, this NK-mediated myeloid conversion was also apparent in cultures after tumor cell depletion and was further enhanced by combining NK cells with R848. Moreover, NK cells, and to a greater extent, the combination of NK cells and R848, triggered CD8 and CD4 T-cell activation as well as a reduction in activated regulatory T cell rates. Finally, the combination of NK cells and R848 induced a pro-inflammatory shift in the cytokine release profile resulting in higher levels of interferon (IFN)-γ, interleukin (IL)-2, IL-12p70, and IFN-α as well as a reduction in IL-6, in both pCRC and mCRC cultures.
CONCLUSION
Allogeneic NK cells engaged in favorable myeloid crosstalk, displayed effective antitumor activity and, when combined with R848, induced a pro-inflammatory shift of the CRC TME. These findings prompt the investigation of NK cells and R848 as a combination therapy for solid tumors.
Topics: Humans; Monocytes; Dendritic Cells; Killer Cells, Natural; Interleukin-12; Colorectal Neoplasms; Hematopoietic Stem Cell Transplantation; Tumor Microenvironment
PubMed: 38056896
DOI: 10.1136/jitc-2023-007554 -
Biomolecules Oct 2023The field of cardio-immunology has emerged from discoveries that define roles for innate and adaptive immune responses associated with myocardial inflammation and heart... (Review)
Review
The field of cardio-immunology has emerged from discoveries that define roles for innate and adaptive immune responses associated with myocardial inflammation and heart failure. Dendritic cells (DCs) comprise an important cellular compartment that contributes to systemic immune surveillance at the junction of innate and adaptive immunity. Once described as a singular immune subset, we now appreciate that DCs consist of a heterogeneous pool of subpopulations, each with distinct effector functions that can uniquely regulate the acute and chronic inflammatory response. Nevertheless, the cardiovascular-specific context involving DCs in negotiating the biological response to myocardial injury is not well understood. Herein, we review our current understanding of the role of DCs in cardiac inflammation and heart failure, including gaps in knowledge and clinical relevance.
Topics: Humans; Heart Failure; Myocarditis; Inflammation; Adaptive Immunity; Dendritic Cells
PubMed: 37892217
DOI: 10.3390/biom13101535 -
Journal For Immunotherapy of Cancer Nov 2023Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor...
Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade.
BACKGROUND
Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.
METHODS
ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.
RESULTS
Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.
CONCLUSIONS
These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.
Topics: Humans; Female; Mice; Animals; CD4-Positive T-Lymphocytes; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Ovarian Neoplasms; Dendritic Cells; Tumor Microenvironment
PubMed: 37918918
DOI: 10.1136/jitc-2023-007661 -
Frontiers in Immunology 2023Acute-on-Chronic Liver Failure (ACLF) patients experience systemic inflammation as well as immune dysfunction and exhaustion. The phenotype and functionality of...
Comparative analysis of monocyte-derived dendritic cell phenotype and T cell stimulatory function in patients with acute-on-chronic liver failure with different clinical parameters.
BACKGROUND
Acute-on-Chronic Liver Failure (ACLF) patients experience systemic inflammation as well as immune dysfunction and exhaustion. The phenotype and functionality of monocyte-derived dendritic cells in ACLF patients with different clinical parameters have not been elucidated.
METHODS
This study included 37 cases of ACLF, 20 cases of Chronic Hepatitis B (CHB) patients, and 12 healthy controls. Demographic and laboratory parameters were collected from the enrolled patients. Peripheral blood samples were obtained from the participants. Monocyte-derived dendritic cells were induced and cultured, followed by co-culturing with T cells from the patients. Cell surface markers and intracellular markers were analyzed using flow cytometry. The relationship between these markers and clinical parameters was compared.
RESULTS
Our study found that ACLF patients had lower expression levels of HLA-DR, CD86, and CD54 on monocyte-derived dendritic cells compared to both CHB patients and healthy controls. IL-4, GM-CSF, and alcohol were found to promote the expression of HLA-DR, CD86, and CD54 on monocyte-derived dendritic cells. In ACLF patients, higher levels of procalcitonin (PCT), lower levels of albumin, decreased prothrombin activity and deceased patients were associated with lower expression of HLA-DR, CD86, and CD54 on monocyte-derived dendritic cells. Peripheral blood mononuclear cells (PBMCs), after removing adherent cells, were co-cultured with monocyte-derived DC. Our study revealed that patients with infection and low albumin levels exhibited a decreased proportion of T cell subsets within PBMCs. Additionally, these patients' T cells showed lower levels of Ki-67 and interferon-gamma (IFN-γ) production.
CONCLUSION
ACLF patients exhibit varying clinical states, with differences in the phenotype and the ability of monocyte-derived dendritic cells to stimulate T cells. Alcohol can stimulate the maturation of monocyte-derived dendritic cells.
Topics: Humans; Monocytes; Acute-On-Chronic Liver Failure; Leukocytes, Mononuclear; HLA-DR Antigens; Phenotype; Dendritic Cells; Albumins
PubMed: 38111573
DOI: 10.3389/fimmu.2023.1290445 -
Clinical Cancer Research : An Official... May 2024Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been...
PURPOSE
Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed.
EXPERIMENTAL DESIGN
We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model.
RESULTS
An aPD1-resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen-specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1-resistant tumors compared with sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1-resistant model, intratumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T-cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1-resistant model, enhanced cDC1 tumor infiltration, restored antigen-specific responses, and recovered sensitivity to aPD1 treatment.
CONCLUSIONS
These data highlight the contribution of tumor-infiltrating cDC1 in HNSCC aPD1 response and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in patients with HNSCC.
Topics: Animals; Dendritic Cells; Mice; Humans; Head and Neck Neoplasms; Drug Resistance, Neoplasm; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Chemokine CCL5; Antibodies, Monoclonal, Humanized; Disease Models, Animal; Neoadjuvant Therapy; Female; Cell Line, Tumor
PubMed: 38372707
DOI: 10.1158/1078-0432.CCR-23-3477 -
Biomolecules Sep 2023The aim of the study was to compare the distribution of corneal and conjunctival epithelial dendritic cells (DCs) in vernal keratoconjunctivitis (VKC), allergic...
The aim of the study was to compare the distribution of corneal and conjunctival epithelial dendritic cells (DCs) in vernal keratoconjunctivitis (VKC), allergic conjunctivitis (AC), and non-allergic controls to examine if the allergy type causes differences in immune cell activation. The prospective study included 60 participants: 20 with VKC, 20 with AC, and 20 non-allergic controls. In vivo confocal microscopy was performed on the right eye. The locations scanned included the corneal centre, inferior whorl, corneal periphery, corneal limbus, and bulbar conjunctiva. The DCs were counted manually, and their morphology was assessed for the largest cell body size, the presence of dendrites, and the presence of long and thick dendrites. The DC density was higher in VKC and AC compared to non-allergic group at all locations ( ≤ 0.01) except at the inferior whorl. The DC density in VKC participants was significantly higher than in AC at the limbus ( < 0.001) but not at other locations. Both the AC and the VKC group had larger DC bodies at the corneal periphery and limbus compared to the non-allergic group ( ≤ 0.03). The study found a higher proportion of participants with DCs exhibiting long dendrites at both the corneal periphery in AC ( = 0.01) and at the corneal centre, periphery, and limbus in VKC, compared to the non-allergic group ( ≤ 0.001). In conclusion, a higher DC density at the limbus may be a marker of more severe VKC. DCs with larger cell bodies and a greater proportion of participants with DCs displaying long dendrites can be potential markers to differentiate allergy from non-allergy, and more severe forms of allergy from milder forms.
Topics: Humans; Conjunctivitis, Allergic; Prospective Studies; Conjunctiva; Cornea; Dendritic Cells
PubMed: 37892151
DOI: 10.3390/biom13101469