scholarly journals Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Jeffrey H. Lin ◽  
Austin P. Huffman ◽  
Max M. Wattenberg ◽  
David M. Walter ◽  
Erica L. Carpenter ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Intraepithelial Neoplasia ◽  
Underlying Mechanism ◽  
T Cell Response ◽  
Pancreatic Carcinogenesis ◽  
Tumor Outgrowth ◽  
Systemic Onset

Type 1 conventional dendritic cells (cDC1s) are typically thought to be dysregulated secondarily to invasive cancer. Here, we report that cDC1 dysfunction instead develops in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre–driven (KPC) mouse model of pancreatic cancer. cDC1 dysfunction is systemic and progressive, driven by increased apoptosis, and results in suboptimal up-regulation of T cell–polarizing cytokines during cDC1 maturation. The underlying mechanism is linked to elevated IL-6 concomitant with neoplasia. Neutralization of IL-6 in vivo ameliorates cDC1 apoptosis, rescuing cDC1 abundance in tumor-bearing mice. CD8+ T cell response to vaccination is impaired as a result of cDC1 dysregulation. Yet, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, decreases cDC1 apoptosis, and repairs cDC1 maturation to drive superior control of tumor outgrowth. Our study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation during pancreatic carcinogenesis and suggests therapeutically tractable strategies toward cDC1 repair.

scholarly journals Acidosis-Induced TGF-β2 Production Promotes Lipid Droplet Formation in Dendritic Cells and Alters Their Potential to Support Anti-Mesothelioma T Cell Response

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1284
Author(s):  
Natalia Trempolec ◽  
Charline Degavre ◽  
Bastien Doix ◽  
Davide Brusa ◽  
Cyril Corbet ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lipid Droplet ◽  
T Cell Activation ◽  
Cell Response ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
T Cell Response ◽  
Mesenchymal Transition

For poorly immunogenic tumors such as mesothelioma there is an imperious need to understand why antigen-presenting cells such as dendritic cells (DCs) are not prone to supporting the anticancer T cell response. The tumor microenvironment (TME) is thought to be a major contributor to this DC dysfunction. We have reported that the acidic TME component promotes lipid droplet (LD) formation together with epithelial-to-mesenchymal transition in cancer cells through autocrine transforming growth factor-β2 (TGF-β2) signaling. Since TGF-β is also a master regulator of immune tolerance, we have here examined whether acidosis can impede immunostimulatory DC activity. We have found that exposure of mesothelioma cells to acidosis promotes TGF-β2 secretion, which in turn leads to LD accumulation and profound metabolic rewiring in DCs. We have further documented how DCs exposed to the mesothelioma acidic milieu make the anticancer vaccine less efficient in vivo, with a reduced extent of both DC migratory potential and T cell activation. Interestingly, inhibition of TGF-β2 signaling and diacylglycerol O-acyltransferase (DGAT), the last enzyme involved in triglyceride synthesis, led to a significant restoration of DC activity and anticancer immune response. In conclusion, our study has identified that acidic mesothelioma milieu drives DC dysfunction and altered T cell response through pharmacologically reversible TGF-β2-dependent mechanisms.

scholarly journals Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer

2011 ◽  
Vol 18 (4) ◽  
pp. 571-579 ◽  
Author(s):  
Soumyabrata Roy ◽  
Shyamal Goswami ◽  
Anamika Bose ◽  
Krishnendu Chakraborty ◽  
Smarajit Pal ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dendritic Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Stage Iiib ◽  
Immune Functions ◽  
Cell Functions

ABSTRACTMyeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients.In vitroNLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is notedin vitroat a fairly advanced stage of CaCx, and thus, further exploration ofex vivoandin vivoDC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.

Selective Disruption of PU.1 in Mature Dendritic Cells Affects Their Tissue Distribution and T Cell Homeostasis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 518-518
Author(s):  
Tadafumi Iino ◽  
Hiromi Iwasaki ◽  
Kentaro Kohno ◽  
Shin-ichi Mizuno ◽  
Yojiro Arinobu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
T Cell Response ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Hematopoietic Stem

Abstract Abstract 518 PU.1, a hematopoietic transcription factor, is indispensable for development of conventional dendritic cells (cDCs) from hematopoietic stem cells. However, the function of PU.1 in mature cDC remains unclear. To test the possible role of PU.1 in mature cDCs, we developed mice lacking PU.1 selectively in mature cDCs (DC-PU.1D/D mice) by crossing a PU.1flox mouse line with a transgenic Itgax (CD11c)-Cre strain. In these mice, cDCs were dramatically reduced in spleen, thymus, lymph node, and skin, down to <40%, <25%, <10% and <5% of DCs in control mice respectively, whereas bone marrow cDCs and common dendritic cells progenitors (CDPs) were not affected. Surprisingly, T cell numbers were significantly decreased in DC-PU.1D/D mice, whereas thymic T cell development was normal, suggesting that maintenance of mature T cell pool might be impaired, presumably by dysfunction of PU.1D/D cDCs. In fact, PU.1D/D cDCs failed to efficiently induce ovalbumin-specific T cell response and to produce inflammatory cytokines in response to Toll like receptor (TLR) stimulation both in vitro and in vivo. The intravenous transfer of spleen PU.1D/D cDCs failed to repopulate the spleen of recipient mice, suggesting their poor survival in vivo. Furthermore, the expression of critical molecules for inflammatory responses was downregulated in PU.1D/D cDCs as compared to normal cDCs. These molecules included Myd88 and NFkB that are downstream molecules of TLR signaling, CD86 that is required for T cell stimulation, and CCR7 that is required for cDC migration. These results clearly show that PU.1 is required for development of the functional cDC pool, and the cDC pool plays a critical role in T cell homeostasis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti–human DEC205 monoclonal antibody

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3828-3838 ◽  
Author(s):  
Cheolho Cheong ◽  
Jae-Hoon Choi ◽  
Laura Vitale ◽  
Li-Zhen He ◽  
Christine Trumpfheller ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Interleukin 2 ◽  
T Cell Response ◽  
Human Immunoglobulin ◽  
Polycytidylic Acid ◽  
Protein Vaccines

Abstract Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-γ– and interleukin-2–producing CD4+ T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of anti-human immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8+ T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects.

scholarly journals Antigen Requirements for Efficient Priming of CD8+ T Cells by Leishmania major-Infected Dendritic Cells

2005 ◽  
Vol 73 (10) ◽  
pp. 6620-6628 ◽  
Author(s):  
Sylvie Bertholet ◽  
Alain Debrabant ◽  
Farhat Afrin ◽  
Elisabeth Caler ◽  
Susana Mendez ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Leishmania Major ◽  
Acquired Resistance ◽  
Chimeric Protein ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Transgenic Parasites

ABSTRACT CD4+ and CD8+ T-cell responses have been shown to be critical for the development and maintenance of acquired resistance to infections with the protozoan parasite Leishmania major. Monitoring the development of immunodominant or clonally restricted T-cell subsets in response to infection has been difficult, however, due to the paucity of known epitopes. We have analyzed the potential of L. major transgenic parasites, expressing the model antigen ovalbumin (OVA), to be presented by antigen-presenting cells to OVA-specific OT-II CD4+ or OT-I CD8+ T cells. Truncated OVA was expressed in L. major as part of a secreted or nonsecreted chimeric protein with L. donovani 3′ nucleotidase (NT-OVA). Dendritic cells (DC) but not macrophages infected with L. major that secreted NT-OVA could prime OT-I T cells to proliferate and release gamma interferon. A diminished T-cell response was observed when DC were infected with parasites expressing nonsecreted NT-OVA or with heat-killed parasites. Inoculation of mice with transgenic parasites elicited the proliferation of adoptively transferred OT-I T cells and their recruitment to the site of infection in the skin. Together, these results demonstrate the possibility of targeting heterologous antigens to specific cellular compartments in L. major and suggest that proteins secreted or released by L. major in infected DC are a major source of peptides for the generation of parasite-specific CD8+ T cells. The ability of L. major transgenic parasites to activate OT-I CD8+ T cells in vivo will permit the analysis of parasite-driven T-cell expansion, differentiation, and recruitment at the clonal level.

EXOSOMES CAPTURED, PROCCESED AND EXCHANGED BY SPLENIC DENDRITIC CELLS SPREAD ALLO – PEPTIDE BETWEEN DCS AND AMPLIFY ANTI DONOR T CELL RESPONSE IN VIVO.

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 179
Author(s):  
A Montecalvo ◽  
W J. Shufesky ◽  
S J. Di Vito ◽  
A T. Larregina ◽  
D Beer Stolz ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response

Identification of CD8α+CD11c− lineage phenotype-negative cells in the spleen as committed precursor of CD8α+ dendritic cells

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 569-577 ◽  
Author(s):  
Yong Wang ◽  
Yanyun Zhang ◽  
Hiroyuki Yoneyama ◽  
Nobuyuki Onai ◽  
Taku Sato ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Messenger Rna ◽  
Critical Role ◽  
Interferon Γ ◽  
T Cell Response ◽  
Interleukin 12 ◽  
Cellular Immune

Abstract CD8α+ dendritic cells (DCs) represent a functionally distinct DC subset in vivo, which plays a critical role in initiating various cellular immune responses. However, the committed precursor of CD8α+ DCs remains to be identified. We reported here that murine splenic CD8α+CD11c− lineage phenotype (Lin)− cells could differentiate into CD8α+DCs in vivo after intravenous transplantation. Immunohistochemistry staining showed that donor-derived DCs mainly located in T-cell areas of the spleen. Functionally, these CD8α+CD11c−Lin− cell–derived DCs were capable of stimulating allogenic T-cell response, as well as secreting bioactive interleukin 12 p70 and interferon γ. Freshly isolated CD8α+CD11c−Lin− cells expressed CC chemokine receptor (CCR)2, CCR5, and CCR7 messenger RNA, whereas CD8α+ DCs derived from CD8α+CD11c−Lin− cells further obtained the expression of CCR6 and macrophage-derived chemokine. Flow cytometry analysis showed that CD8α+CD11c−Lin− cells were identified in bone marrow and lymph nodes. Moreover, transplanted splenic CD8α+CD11c−Lin− cells could also home to thymus and lymph nodes and were capable of developing into CD8α+ DCs in these locations. However, CD8α+CD11c−Lin−cells failed to differentiate into CD8α− DCs, T cells, natural killer cells, or other myeloid lineage cells in irradiated chimeras. Taken together, all these findings suggest that CD8α+CD11c−Lin− cells are a committed precursor of CD8α+ DCs.

scholarly journals Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity

2021 ◽  
Vol 9 (5) ◽  
pp. e002155
Author(s):  
Zining Wang ◽  
Feifei Xu ◽  
Jie Hu ◽  
Hongxia Zhang ◽  
Lei Cui ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Therapeutic Efficacy ◽  
Antitumor Immunity ◽  
Critical Role ◽  
T Cell Response

BackgroundDendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.MethodsIn vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and Batf3−/− mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.ResultsBy screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and Chop expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.ConclusionsOur findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.

scholarly journals Expression of vFLIP in a Lentiviral Vaccine Vector Activates NF-κB, Matures Dendritic Cells, and Increases CD8+ T-Cell Responses

2008 ◽  
Vol 83 (4) ◽  
pp. 1555-1562 ◽  
Author(s):  
Helen M. Rowe ◽  
Luciene Lopes ◽  
Najmeeyah Brown ◽  
Sofia Efklidou ◽  
Timothy Smallie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Therapy ◽  
T Cell Response ◽  
Vaccine Vector ◽  
Interleukin 12 ◽  
Mouse Bone Marrow ◽  
Dc Maturation

ABSTRACT Lentiviral vectors deliver antigens to dendritic cells (DCs) in vivo, but they do not trigger DC maturation. We therefore expressed a viral protein that constitutively activates NF-κB, vFLIP from Kaposi's sarcoma-associated herpesvirus (KSHV), in a lentivector to mature DCs. vFLIP activated NF-κB in mouse bone marrow-derived DCs in vitro and matured these DCs to a similar extent as lipopolysaccharide; costimulatory markers CD80, CD86, CD40, and ICAM-1 were upregulated and tumor necrosis factor alpha and interleukin-12 secreted. The vFLIP-expressing lentivector also matured DCs in vivo. When we coexpressed vFLIP in a lentivector with ovalbumin (Ova), we found an increased immune response to Ova; up to 10 times more Ova-specific CD8+ T cells secreting gamma interferon were detected in the spleens of vFLIP_Ova-immunized mice than in the spleens of mice immunized with GFP_Ova. Furthermore, this increased CD8+ T-cell response correlated with improved tumor-free survival in a tumor therapy model. A single immunization with vFLIP_Ova also reduced the parasite load when mice were challenged with OVA-Leishmania donovani. In conclusion, vFLIP from KSHV is a DC activator, maturing DCs in vitro and in vivo. This demonstrates that NF-κB activation is sufficient to induce many aspects of DC maturation and that expression of a constitutive NF-κB activator can improve the efficacy of a vaccine vector.

scholarly journals MHC class II–restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell–mediated autoimmunity

2010 ◽  
Vol 207 (9) ◽  
pp. 1891-1905 ◽  
Author(s):  
Magali Irla ◽  
Natalia Küpfer ◽  
Tobias Suter ◽  
Rami Lissilaa ◽  
Mahdia Benkhoucha ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Plasmacytoid Dendritic Cells ◽  
T Cell Response ◽  
Lymphoid Tissues ◽  
Capture Process

Although plasmacytoid dendritic cells (pDCs) express major histocompatibility complex class II (MHCII) molecules, and can capture, process, and present antigens (Ags), direct demonstrations that they function as professional Ag-presenting cells (APCs) in vivo during ongoing immune responses remain lacking. We demonstrate that mice exhibiting a selective abrogation of MHCII expression by pDCs develop exacerbated experimental autoimmune encephalomyelitis (EAE) as a consequence of enhanced priming of encephalitogenic CD4+ T cell responses in secondary lymphoid tissues. After EAE induction, pDCs are recruited to lymph nodes and establish MHCII-dependent myelin-Ag–specific contacts with CD4+ T cells. These interactions promote the selective expansion of myelin-Ag–specific natural regulatory T cells that dampen the autoimmune T cell response. pDCs thus function as APCs during the course of EAE and confer a natural protection against autoimmune disease development that is mediated directly by their ability to present of Ags to CD4+ T cells in vivo.

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