DC Function Research Articles

Profound deficiencies in mature blood and bone marrow progenitor dendritic cells in Chronic Lymphocyticcytic Leukemia patients.

Chronic lymphocytic leukemia (CLL) patients are immunocompromised and highly vulnerable to serious recurrent infections. Conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are principal sensors of infection and are essential in orchestrating innate and adaptive immune responses to resolve infection. This study identified significant deficiencies in six functionally distinct DC subsets in blood of untreated CLL (UT-CLL) patients and selective normalization of pDCs in response to acalabrutinib (a Bruton tyrosine kinase inhibitor) therapy. DCs are continuously replenished from hematopoiesis in bone marrow (BM). Four BM developmental intermediates that give rise to cDCs and pDCs were examined and significant reductions of these were identified in UT-CLL patients supporting a precursor/progeny relationship. The deficiencies in blood DCs and BM DC progenitors were significantly associated with alterations in the Flt3/FL signaling pathway critical to DC development and function. Regarding clinical parameter, cDC subset deficiencies are associated with adverse prognostic indicators of disease progression, including IGHV mutation, CD49d, CD38, and ZAP-70 status. Importantly, UT-CLL patients with shared DC subset deficiencies had shorter time-to-first treatment (TTFT), uncovering a profound alteration in innate immunity with the potential to instruct therapeutic decision-making.

Preparation of a Plasma‐Induced Dendritic Cell Vaccine and its Anti‐Tumor Immunity in a Murine Model of Melanoma

AbstractDendritic cell (DC) vaccines play an important role in anti‐tumor immunotherapy. Tumor‐associated cells or cytokines in the tumor microenvironment (TME) can inhibit the antigen‐presenting function of DC. Immunogenic cell death (ICD) can enhance the uptake and presentation of tumor antigens by DC. This study investigates the maturation mechanism of DC induced by low‐temperature plasma (LTP), as well as the therapeutic and protective effects of LTP‐induced DC vaccine in a tumor model. DC2.4 that is co‐cultured with LTP‐treated B16F10 (LTP‐B16) or with these supernatants exhibited decreased phagocytic activity, increased production of cytokines (IL‐12, IL‐6, TNF‐α, and IL‐1β), and increased expression of cell surface activation markers (CD80, CD86, and MHC II). The expression of CD80+/CD86+ is decreased after pre‐treatment with TLR4 and NF‐κB (p65) inhibitors, respectively. In vivo, trials indicated that the LTP‐induced DC vaccine‐induced anti‐tumor immunity and, when combined with cisplatin, synergistically reduced tumor growth.

Characterizations of minimal elements of upper support with applications in minimizing DC functions

Abstract In this study, we discuss on the problem of minimizing the differences of two non-positive valued increasing, co-radiant and quasi-concave (ICRQC) functions defined on X X (where X X is a real locally convex topological vector space). For this purpose, we first gave different characterizations of the upper support set’s minimal elements of non-positive co-radiant functions. Then, we presented sufficient and necessary conditions for the global minimizers of the differences of two non-positive ICRQC functions.

Abstract 3922: Quaking modulates anti-tumor immunity by regulating antigen processing and presentation in dendritic cells

Abstract Dendritic cells are essential players in anti-tumor immunity. One of their critical roles is to process and present tumor associated antigens to T cells, thereby inducing antigen-specific T cell response. However, cellular factors and molecular pathways regulating antigen processing and presentation by DCs are not fully understood.Here, we revealed a potential regulatory role of a transcriptional co-activator, Quaking (QKI), and its binding partner, PPARδ in antigen processing and presentation by DCs. Consistent with our previous studies in neural stem cells and microglia, we found QKI and PPARδ enhance phagocytosis in DCs by upregulating genes involved in the formation of phagosome and endosomes. QKI- or PPARδ-deficient DCs showed reduced CD8+ T cell priming capacity in vitro. In vivo tumor models suggested DC-specific knocking out of QKI or PPARδ promoted the tumor growth. Furthermore, ablation of QKI or PPARδ in DCs limited the effectiveness of immune checkpoint blockade in multiple tumor models.Together, these revealed a transcriptional regulation of antigen processing and presentation by DCs through QKI and PPARδ. Our data also suggested that perturbing this important function of DC would subvert their anti-tumor activity, highlighting the pivotal role of DCs in an effective anti-tumor immune response. Citation Format: Yating Li, Jian Hu, Cassian Yee. Quaking modulates anti-tumor immunity by regulating antigen processing and presentation in dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3922.

Abstract 1503: Melanoma-derived lymphatic extracellular vesicles suppress dendritic cell differentiation and maturation in the sentinel lymph node

Abstract Spread to regional lymph nodes is the most common site of metastasis from melanoma and almost all solid tumors. Lymphatic metastases begin in the first lymph nodes draining from the primary tumor, i.e., the sentinel lymph nodes (SLN), preceded by the development of the premetastatic niche (PMN) initiated by primary cutaneous melanoma. Melanoma mediators are known to play a critical role in developing the PMN through the immune subversion in SLN. The DCs are a vital component of LN immunity that directly relates to eliciting T-cell functions. Our multiplex immunofluorescence (MxIF) analysis of SLNs indicates significantly decreased levels of DCs and cytotoxic-T cells in both core and interface areas of tumors in recurred patients treated with immunotherapy compared to non-recurred melanoma patients. The goal of this study is to determine whether the lymphatic extracellular vesicles (L-EVs) of melanoma patients regulate DC tolerization in SLN in order to stimulate the development of PMN. To identify whether L-EVs stimulate DC suppression, we extracted L-EVs from the lymphatic fluid of patients with melanoma downstream of primary cutaneous melanomas, compared it with controls (non-malignant post-operative fluid collected from the lymph node dissection field, and evaluated their effect on DC maturation by challenging these L-EVs in monocytic (CD14+) and hematopoietic stem cells (CD34+) cells. We found that L-EVs derived from melanoma patients suppress differentiation of CD11c+HLA-DR+ DCs and their maturation (defined by CD83 and CD86) compared to control L-EVs in CD14+ based DC maturation assay. We also found a reduction of conventional type 1 DC (cDC1) in CD34+-based DC maturation assay those challenged with patients’ L-EVs compared to control. To understand the mechanism of DC suppression in patients' L-EVs, we also conducted a total RNA sequencing analysis of subsets of DCs from maturation experiments to evaluate differently regulated transcriptomic profiles. The gene ontology analysis indicates that patient-derived L-EVs interfere with tRNA processing, oncostatin M & IL-10 signaling, and other immunoregulatory pathways to alter the hematopoietic cell lineage pathways in the DC maturation. Furthermore, the proteomic analysis of L-EVs also indicated several differentially regulated cargo-identified proteins in patient L-EVs, which are associated with immunomodulation, including regulation of DC function compared to control L-EVs. In conclusion, our study revealed that the patient's L-EVs carry differential proteomic cargoes secreted by cutaneous melanoma, which may be involved in regulating DC differentiation and maturation to diminish their functions and support the developing PMN in SLN. Citation Format: Shankar Suman, Wendy K. Nevala, James W. Jakub, Ray Guo, Alexey A. Leontovich, Raymond M. Moore, Chathu L. Atherton, Liyi Geng, Jeffrey E. Johnson, Sarah A. McLaughlin, Svetomir N. Markovic. Melanoma-derived lymphatic extracellular vesicles suppress dendritic cell differentiation and maturation in the sentinel lymph node [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1503.

Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells

BackgroundDendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs...

Differentiation, maturation, and collection of THP-1-derived dendritic cells based on a PEG hydrogel culture platform

PurposeDendritic cell (DC) is a spearhead responsible for immune response and surrounded by extracellular matrix in three-dimensional (3D) tissue. Nevertheless, conventional DC culture has relied on suspension or two-dimensional (2D) tissue culture plate (TCP)-based culture system. This culture condition often fails to recapitulate the physiological behavior of DC in real tissue. In this work, the effect of culture condition on DC physiology was explored with varying 3D hydrogel property (i.e., degradability, adhesion, and stiffness). In particular, DC differentiation and maturation in 3D were evaluated comparing the conventional TCP-based culture condition.MethodTHP-1 cells were encapsulated in poly(ethylene glycol) (PEG) hydrogel via thiol-ene photocrosslinking with non-degradable or proteolytically degradable peptide crosslinker. Hydrogel stiffness was manipulated by controlling the concentration of crosslinker. The metabolic activities and cytotoxicity of the encapsulated cells were measured by resazurin and Live/Dead assays, respectively. Cell harvesting was conducted via enzymatic degradation using α-chymotrypsin, and differentiation and maturation of the liberated DCs were evaluated by quantitative polymerase chain reaction and flow cytometry.ResultsTHP-1 cells well proliferated in the soft degradable hydrogel with a higher metabolic activity. However, the stiff matrix inhibited cell growth in 3D. The gene expression assay indicated that the 3D hydrogel condition was superior to 2D culture in terms of differentiation and maturation of DC. Interestingly, the stiffness of matrix was important factor in DC function. In the stiff hydrogel, the expression levels of differentiation and maturation markers were higher compared to the low stiffness hydrogel. The mature DCs caged in the hydrogel matrix were harvested after short enzymatic digestion of hydrogel and the liberated cells had over 90% viability. The flow cytometric result revealed that the proportion of CD80 + /CD86 + cells from the stiff hydrogel was relatively higher than cells either from 2D or soft hydrogel in 3D.ConclusionThe collected evidence indicated that the proteolytically degradable PEG hydrogel matrix promoted DC differentiation and maturation. In addition, the matrix stiffness control could manipulate the marker expressions of differentiation and maturation. Particularly, the mature DC was successfully collected from the hydrogel matrix. These results highlighted the PEG hydrogel-based DC culture might be a useful tool for potential DC-based immunotherapies.

Role of solute carrier transporters in regulating dendritic cell maturation and function.

Dendritic cells (DCs) are specialized antigen-presenting cells that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases.

In situ lipid-loading activates peripheral dendritic cell subsets characterized by cellular ROS accumulation but compromises their capacity to prime naïve T cells

Background and aimsDendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established. MethodsIn this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr−/−) mice on separate DC subsets, their compartmentalization and functionality. ResultsWhile hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4+ T cells. ConclusionOur data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.

Engineered Nanovesicles Expressing Bispecific Single Chain Variable Fragments to Protect against SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in high morbidity and mortality rates worldwide. Although the epidemic has been controlled in many areas and numerous patients have been successfully treated, the risk of reinfection persists due to the low neutralizing antibody titers and weak immune response. To provide long-term immune protection for infected patients, novel bispecific CB6/dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (SIGN) nanovesicles (NVs) were constructed to target both the SARS-CoV-2 spike protein (S) and the DC receptors for virus neutralization and immune activation. Herein, we designed NVs expressing both CB6 and DC-SIGN single chain variable fragments (scFvs) on the surface to block SARS-CoV-2 invasion and activate DC function. Monophosphoryl lipid A (MPLA) was loaded into the CB6/DC-SIGN NVs as an adjuvant to promote this process. The CB6/DC-SIGN NVs prevented a pseudovirus expressing the S protein from infecting the target cells expressing high levels of angiotensin-converting enzyme 2 in vitro. Additionally, CB6/DC-SIGN NVs admixed with S-expressing pseudoviruses activated the DCs, which was promoted by the adjuvant MPLA loaded in the NVs. Using a mouse model, we also confirmed that the CB6/DC-SIGN NVs effectively improved the neutralizing antibody titer and inhibited the growth of tumors expressing the S protein after 3 weeks of treatment. This potential NV-based treatment not only exerts a blocking effect by binding the S protein in the short term but may also provide patients with long-term protection against secondary infections.

Circular RNA MAP2K2-modified immunosuppressive dendritic cells for preventing alloimmune rejection in organ transplantation.

Long-term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long-term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to prevent immune rejection. We hypothesized that knockdown of circMAP2K2 induces immunosuppressive DCs and that treatment with circMAP2K2 silenced-DCs can prevent alloimmune rejection. DCs were cultured and transfected with siRNA for circMAP2K2. circMAP2K2 levels were measured by qRT-PCR. DC's maturation and immune function were assessed by flow cytometry and mixed lymphocyte reactions. The function of circMAP2K2 was illustrated by a series of RIP and IP. The therapeutics of engineered DCs was tested in a mouse heart transplantation model. We found that circMAP2K2 was highly expressed in mature DCs. Knockdown of circMAP2K2 reduced expression of MHCII, CD40 and CD80, attenuated the ability of DCs to activate allogeneic naïve T cells, and enhanced CD4+CD25+FOXP3+ regulatory T cells (Treg). circMAP2K2-induced immunosuppressive DCs by interacting with SENP3. Treatment with circMAP2K2-knockdown DCs attenuated alloimmune rejection and prolonged allograft survival in a murine heart transplantation model. The immune suppression induced in vivo was donor-antigen specific. In conclusion, knockdown of circMAP2K2 can induce immunosuppressive DCs which are able to inhibit overactive immune response, highlighting a new promising therapeutic approach for immune disorder diseases.

Enactment of Deep Reinforcement Learning Control for Power Management and Enhancement of Voltage Regulation in a DC Micro-Grid System

DC micro-grids are gaining more attention and becoming more predominant due to its robustness and ease of control. To confront the stability issues of the DC Micro-grid system, a model free intellectual Control approach is proposed and recognized with a deep Q-learning controller to influence the functions of DC–DC boost converter. This self-reliant model of deep Q-learning controller establish a suitable communication link among the agent-environment by applying the reward/penalty algorithm for attaining the stable output voltage with its training statistics. Upon learning the state of agent, an optimal proposal is defined by the controller to attain the stabilized voltage at the output for all possible operating scenarios. The simulation and experimental studies validate the performance of the controller with higher accuracy, reduced overshoot, and faster settling time upon the transient states.

Directional Differentiability, Coexhausters, Codifferentials and Polyhedral DC Functions

Codifferentials and coexhausters are used to describe nonhomogeneous approximations of a nonsmooth function. Despite the fact that coexhausters are modern generalizations of codifferentials, the theories of these two concepts continue to develop simultaneously. Moreover, codifferentials and coexhausters are strongly connected with DC functions. In this paper we trace analogies between all these objects, and prove the equivalence of the boundedness and optimality conditions described in terms of these notions. This allows one to extend the results derived in terms of one object to the problems stated via the other one. Another contribution of this paper is the study of connection between nonhomogeneous approximations and directional derivatives and formulate optimality conditions in terms of nonhomogeneous approximations.

Elucidating the role of heat shock protein receptor CD91 on antigen presenting cells during cancer immunosurveillance

Abstract The premise of immunosurveillance is that the immune system, particularly by T cells, allows detection and elimination of emerging tumor cells. However, the mechanisms that allow efficient T cell priming against nascent tumors despite limited antigen availability remain unclear. We have shown that immunogenic heat shock proteins (HSPs) such as gp96 and their receptor CD91 are one such mechanism. HSPs efficiently chaperone minute levels of peptides from tumors to elicit antigen-specific immunity. Cross presentation of HSP-chaperoned peptides by CD91 +dendritic cells is a key mechanism for priming T cell responses. Diverse DC subsets vary in their capacity to modulate such anti-tumor immune responses. In this project, we aim to understand which CD91 +DC subset(s) is/are important for HSP-mediated cancer immunosurveillance. We generated mouse strains with deletion of CD91 on specific DC subsets. cDC1s are thought to be superior cross-presenters that excel in activation of cytotoxic lymphocytes. CD91 deletion in cDC1 render mice highly susceptible to chemically induced tumors. To better understand the CD91-HSP pathway, we tracked the dispersal of tumor-derived gp96 among myeloid cells using tumor cells that express EGFP-tagged gp96. We show that migratory DC subpopulations, such as CD103 +(cDC1) dendritic cells acquire gp96 from the tumor microenvironment, while a different DC subset (CD11b +CD11c +) transfers protective antitumor immunity. The hand-off of tumor-derived gp96 between migratory and lymph node resident DCs is currently under investigation. These results advance our understanding of the HSP-CD91 pathway and its role in DC function which can have significant implications for cancer prognosis and therapy. 5R01CA233803-04

Immune chaperone modulates dendritic cell functions in the tumor microenvironment

Abstract Dendritic cells (DCs) are central regulators of the adaptive immune response, thereupon necessary for T cell-mediated cancer immunity. To improve anti-tumor response, strategies to stimulate T cell response create new opportunities in DC cell biology, where DC maturation and antigen presentation are paramount. DC1 subtype is known for antigen-cross presentation to CD8 +T cells and the DC2 subtype to CD4 +T-cells. Previous studies showed that the immune chaperone GP96 plays a pivotal role in the processes of innate receptors. As a subject of interest from our lab, the GP96 client network offers potential targets to be explored for improving DC functions. We reported an increase in DC2 infiltration on the tumor side and a reduction of tumor growth in DC-specific GP96 deficient mice. Notwithstanding, the mechanism of GP96 in regulating DC functions is the subject of our study. By using in vitro approach, our study shows improvement in DC differentiation through gene expression assay, where DC subtypes display differential dependence on ER chaperone proteins. Also, the deletion of GP96 in DCs improves immunostimulatory activation and inhibits regulatory functions. Lastly, GP96 deficient DCs increased OVA antigen uptake and showed less T-cell exhaustion profile from in vivo tumor model. Directly DC activation or bypassing regulatory pathways can unleash T-cell response. Our study provides new insights into the role of GP96 in DCs in directing adaptive immune responses in the tumor microenvironment. This work was supported by the Pelotonia Institute of Immuno-Oncology (PIIO). The work was also supported in part by NIH/NCI (CA193939) and NIH/NIAID (AI125859) and supported by the Flow Cytometry Shared Resource at The Ohio State University Comprehensive Cancer Center and NIH/NCI P30 (CA138313).

A noncanonical NF-kB - β-catenin signaling axis in dendritic cells instructs gut inflammation

Abstract Dendritic cells (DCs) balance intestinal homeostasis against inflammatory insults. In particular, the noncanonical NF-kB pathway, which activates RelB:p52 heterodimers, has been implicated in DC differentiation. However, if DC-intrinsic noncanonical signaling modulates DC function in the inflamed gut remains unclear. Here we report that genetic ablation of the noncanonical signaling in DCs accumulated regulatory T cells in the lamina propria and associated lymph nodes, restraining inflammation in the colitogenic gut. Our mechanistic investigation revealed that an impaired RelB:p52 gene function, rather unexpectedly, augmented the abundance of active β-catenin via impairment of the β-catenin destruction complex. In turn, β-catenin transcriptionally upregulated Raldh2, imparting a retinoic acid gene signature and tolerogenic functions to noncanonical NF-kB-deficient DCs. Indeed, mice possessing DC-intrinsic noncanonical signaling defects exhibited an increased frequency of β-catenin +DCs in the gut and resilience to chemical induced experimental colitis. Taken together, we chart a novel crosstalk between noncanonical NF-kB signaling and the β-catenin pathway that instructs tolerogenic DC functions and modulates inflammation in the gut. National Institute of Immunology Core funding and BT/PR36631/BRB/10/1862/2020, Department of Biotechnology (DBT).

138 Oral tolerance inhibits DTH in the sensitization phase by Treg-mediated suppression of DC functions in skin dLNs

138 Oral tolerance inhibits DTH in the sensitization phase by Treg-mediated suppression of DC functions in skin dLNs

Lung Nodule CT Image Segmentation Model Based on Multiscale Dense Residual Neural Network

To solve the problem of the low segmentation accuracy of lung nodule CT images using U-Net, an improved method for segmentation of lung nodules by U-Net was proposed. Initially, the dense network connection and sawtooth expanded convolution design was added to the feature extraction part, and a local residual design was adopted in the upsampling process. Finally, the effectiveness of the proposed algorithm was evaluated using the LIDC-IDRI lung nodule public dataset. The results showed that the improved algorithm had 7.03%, 14.05%, and 10.43% higher performance than the U-Net segmentation algorithm under the three loss functions of DC, MIOU, and SE, and the accuracy was 2.45% higher compared with that of U-Net. Thus, the proposed method had an effective network structure.

PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control

BackgroundDendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action.MethodsCecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively.ResultsWe found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice.ConclusionOur results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control.

Longitudinal analysis of DC subsets in patients with ovarian cancer: Implications for immunotherapy.

The use of circulating cDC1 to generate anti-cancer vaccines is among the most promising approaches to overcome the limited immunogenicity and clinical efficacy of monocyte-derived DC. However, the recurrent lymphopenia and the reduction of DC numbers and functionality in patients with cancer may represent an important limitation of such approach. In patients with ovarian cancer (OvC) that had received chemotherapy, we previously showed that cDC1 frequency and function were reduced. We recruited healthy donors (HD, n=7) and patients with OvC at diagnosis and undergoing interval debulking surgery (IDS, n=6), primary debulking surgery (PDS, n=6) or at relapse (n=8). We characterized longitudinally phenotypic and functional properties of peripheral DC subsets by multiparametric flow cytometry. We show that the frequency of cDC1 and the total CD141+ DC capacity to take up antigen are not reduced at the diagnosis, while their TLR3 responsiveness is partially impaired in comparison with HD. Chemotherapy causes cDC1 depletion and increase in cDC2 frequency, but mainly in patients belonging to the PDS group, while in the IDS group both total lymphocytes and cDC1 are preserved. The capacity of total CD141+ DC and cDC2 to take up antigen is not impacted by chemotherapy, while the activation capacity upon Poly(I:C) (TLR3L) stimulation is further decreased. Our study provides new information about the impact of chemotherapy on the immune system of patients with OvC and sheds a new light on the importance of considering timing with respect to chemotherapy when designing new vaccination strategies that aim at withdrawing or targeting specific DC subsets.