scholarly journals Engineered Porous/Hollow Burkholderia Pseudomallei Loading Tumor Lysate as a Vaccine

2021 ◽  
Author(s):  
Feng-Ying Huang ◽  
Shu-Zhen Dai ◽  
Jin-Yan Wang ◽  
Ying-Ying Lin ◽  
Cai-Chun Wang ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Tumor Vaccine ◽  
Tumor Lysate ◽  
Adhesion Proteins ◽  
Cross Presentation ◽  
Immunosuppressive Tumor Microenvironment ◽  
Molecular Patterns ◽  
Model Tumor ◽  
Dc Maturation ◽  
Viable Treatment

Abstract Due to its size, shape, and inherent expression of pathogen-associated molecular patterns and invasion-assistant adhesion proteins, Burkholderia pseudomallei can easily attach to, and then be internalized by, dendritic cells (DCs), leading to more efficient antigen cross-presentation if modified as carrier. Herein, we engineered Burkholderia pseudomallei as a porous/hollow carrier (SB) for loading tumor lysates (L) and CpG (C) to be used as a tumor vaccine (SB-LC). We found that the adhesion proteins of Burkholderia pseudomallei promote internalization of the SB-LC vaccine by DCs, and result in enhanced DC maturation and antigen cross-presentation. SB-LC induces robust cellular and humoral antitumor responses that synergistically inhibit tumor growth with minimal adverse side effects in several tumor models. Moreover, SB-LC vaccination reverses the immunosuppressive tumor microenvironment, apparently as a result of CD8+-induced tumor ferroptosis. Thus, SB-LC is a potential model tumor vaccine for translating into a clinically viable treatment option.

scholarly journals Nanoparticle-enhanced chemo-immunotherapy to trigger robust antitumor immunity

2020 ◽  
Vol 6 (35) ◽  
pp. eabc3646 ◽  
Author(s):  
Jingjing Liang ◽  
Huifang Wang ◽  
Wenxiu Ding ◽  
Jianxiang Huang ◽  
Xuefei Zhou ◽  
...  
Keyword(s):  
Triblock Copolymer ◽  
Rational Design ◽  
Antitumor Immunity ◽  
Chemotherapeutic Agent ◽  
Therapeutic Benefit ◽  
Combination Regimen ◽  
Cross Presentation ◽  
New Class ◽  
Immunosuppressive Tumor Microenvironment ◽  
Novel Strategy

Mounting evidence suggests that immunotherapies are a promising new class of anticancer therapies. However, the immunosuppressive tumor microenvironment (TME), poor immunogenicity, and off-target toxicity hinder the broader implementation of immunotherapies. Here, we describe a novel strategy combining chemotherapy and immunotherapy to modulate the TME by systemically and concurrently delivering the chemotherapeutic agent SN38 (7-ethyl-10-hydroxycamptothecin) and the STING agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into tumors using triblock copolymer nanoparticles, named PS3D1@DMXAA, which enhances antigen cross-presentation and induces the conversion of the immunosuppressive TME to immunogenic TME through the newly found synergistic function between SN38 and STING activation. PS3D1@DMXAA thus shows potent therapeutic efficacy in three mice tumor models and elicits remarkable therapeutic benefit when combined with anti–PD-1 therapy. Our engineered nanosystem offers a rational design of an effective immunotherapy combination regimen to convert uninflamed “cold” tumors into “hot” tumors, addressing the major challenges immunotherapies faced.

Leukemic blasts fail to differentiate into mature antigen presenting cells, and may hinder dendritic cell maturation in vitro and in vivo

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10556-10556
Author(s):  
J. Rosenblatt ◽  
R. Stone ◽  
C. Lenahan ◽  
Z. Wu ◽  
B. Vasir ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Vaccine ◽  
Leukemia Cells ◽  
Phenotypic Characteristics ◽  
Gm Csf ◽  
Maturation In Vitro ◽  
Dc Maturation

10556 Background: Dendritic cells (DC) play a key role in the development of tumor specific immune responses. Dendritic cells differentiated from leukemic blasts (LDC) are being explored as a tumor vaccine in AML. We examined the phenotypic and functional characteristics of LDC, the phenotypic characteristics of native DC in AML patients, and the effect of leukemic blasts on the phenotype of DC generated from normal donors. Methods: Leukemia blasts were isolated from peripheral blood of 24 patients with AML. LDC were generated by culturing blasts in the presence of GM-CSF, IL-4 and TNFa for 7 days. The phenotype of circulating DC1 (CD11C+/lin-) and DC2 (CD123+/ lin-) in AML patients was assessed by multichannel FACS analysis. To assess the effect of blasts on DC maturation, adherent mononuclear cells were isolated from normal donors, combined with leukemia cells in a 10:1 ratio, and cultured with GM-CSF, IL-4, and TNFa. Results: LDC demonstrate only modest expression of the costimulatory molecules CD80 and CD86 (mean expression 10% and 32%) and poorly express the maturation marker CD83 (mean expression 4%). Interferon gamma production by autologous T cells was not higher after stimulation with LDC than with blasts. LDC stimlation resulted in a 2 fold increase in both CD4+/CD25+/CD69+ (activated) and CD4+/CD25+/FOXP3+ (regulatory) T cells. Given the inability of leukemia progenitors to differentiate into phenotypically mature DC, we assessed whether leukemia cells directly inhibit differentiation of DC from normal progenitors. Expression of costimulatory molecules was decreased in DC differentiated in the presence of blasts. Mean expression of CD80, CD83, and CD86 was 16%, 2%, 83% and 49%, 10%, 99% for DCs generated in the presence or absence blasts respectively. Phenotypic characteristics of native DC in patients with AML were examined. In 3 experiments, a predominance of DC2 was seen (ratio DC2/DC1 5), and both DC1 and DC2 poorly expressed CD83 (mean expression 9% DC1, 0.9% DC2). Conclusions: LDC have phenotypic and functional deficiencies, limiting their efficacy as a tumor vaccine. Contact with leukemic blasts may inhibit DC maturation in vitro and in vivo, which may contribute to the lack of effective antitumor immunity in AML patients. No significant financial relationships to disclose.

scholarly journals Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells

2015 ◽  
Vol 112 (47) ◽  
pp. 14664-14669 ◽  
Author(s):  
Anand K. Katakam ◽  
Hans Brightbill ◽  
Christian Franci ◽  
Chung Kung ◽  
Victor Nunez ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Lymphoid Organs ◽  
Serine Threonine Kinase ◽  
Cross Presentation ◽  
Inflammatory Stimuli ◽  
Dc Maturation

Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB–inducing kinase) remains unclear. Because NIK-deficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c+ cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8+ T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8+ DCs in vitro, namely antigen cross-presentation to CD8+ T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4+ T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.

Mutated Ras-Transfected, EBV-Transformed Lymphoblastoid Cell Lines as a Model Tumor Vaccine for Boosting T-Cell Responses Against Pancreatic Cancer: A Pilot Trial

2012 ◽  
Vol 23 (12) ◽  
pp. 1224-1236 ◽  
Author(s):  
Boris Kubuschok ◽  
Michael Pfreundschuh ◽  
Rainer Breit ◽  
Frank Hartmann ◽  
Martina Sester ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Cell Lines ◽  
Tumor Vaccine ◽  
Pilot Trial ◽  
T Cell Responses ◽  
Lymphoblastoid Cell Lines ◽  
Cell Responses ◽  
Model Tumor

scholarly journals Yeast-Derived Human Immunodeficiency Virus Type 1 p55gag Virus-Like Particles Activate Dendritic Cells (DCs) and Induce Perforin Expression in Gag-Specific CD8+ T Cells by Cross-Presentation of DCs

2003 ◽  
Vol 77 (19) ◽  
pp. 10250-10259 ◽  
Author(s):  
Yasuko Tsunetsugu-Yokota ◽  
Yuko Morikawa ◽  
Maya Isogai ◽  
Ai Kawana-Tachikawa ◽  
Takashi Odawara ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Interleukin 12 ◽  
Virus Like Particles ◽  
Cross Presentation ◽  
Immunodeficiency Virus ◽  
Dc Maturation

ABSTRACT To evaluate the immunogenicity of human immunodeficiency virus (HIV) type 1 p55 gag virus-like particles (VLPs) released by budding from yeast spheroplasts, we have analyzed the effects of yeast VLPs on monocyte-derived dendritic cells (DCs). Yeast VLPs were efficiently incorporated into DCs via both macropinocytosis and endocytosis mediated by mannose-recognizing receptors, but not the mannose receptor. The uptake of yeast VLPs induced DC maturation and enhanced cytokine production, notably, interleukin-12 p70. We showed that yeast membrane components may contribute to DC maturation partly through Toll-like receptor 2 signaling. Thus, Gag particles encapsulated by yeast membrane may have an advantage in stimulating Gag-specific immune responses. We found that yeast VLPs, but not the control yeast membrane fraction, were able to activate both CD4+ and CD8+ T cells of HIV-infected individuals. We tested the effect of cross-presentation of VLP by DCs in two subjects recruited into a long-term nonprogressor-slow progressor cohort. When yeast VLP-loaded DCs of these patients were cocultured with peripheral blood mononuclear cells for 7 days, approximately one-third of the Gag-specific CD8+ T cells were activated and became perforin positive. However, some of the Gag-specific CD8+ T cells appeared to be lost during in vitro culture, especially in a patient with a high virus load. Our results suggest that DCs loaded with yeast VLPs can activate Gag-specific memory CD8+ T cells to become effector cells in chronically HIV-infected individuals, but there still remain unresponsive Gag-specific T-cell populations in these patients.

scholarly journals Engineered porous/hollow Burkholderia pseudomallei loading tumor lysate as a vaccine

Biomaterials ◽  
2021 ◽  
pp. 121141
Author(s):  
Feng-Ying Huang ◽  
Shu-Zhen Dai ◽  
Jin-Yan Wang ◽  
Ying-Ying Lin ◽  
Cai-Chun Wang ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Tumor Lysate

The influence of harvest method on dendritic cell function and clinical outcomes in a randomized trial of a dendritic cell vaccine to prevent recurrences in high-risk melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9548-9548
Author(s):  
Alexandra Adams ◽  
G. Travis Clifton ◽  
Timothy J. Vreeland ◽  
Anne E. O'Shea ◽  
Patrick M. McCarthy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cell ◽  
Clinical Outcomes ◽  
Phase Iii ◽  
Autologous Tumor ◽  
Rna Seq ◽  
Vaccine Production ◽  
Tumor Lysate ◽  
Blood Draw ◽  
Dc Maturation

9548 Background: A randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine was conducted to prevent recurrence in patients (pts) with resected stage III/IV melanoma. Two methods for dendritic cell (DC) harvest were used for vaccine production, including no pretreatment or pretreatment with granulocyte-colony stimulating factor (G-CSF) in an attempt to reduce blood draw volumes. This analysis investigates differences in clinical outcomes and RNA gene expression between these DC harvest methods for TLPLDC vaccine creation. Methods: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. By investigator/pt choice, pts had 120mL of blood drawn for DC harvest, or pts received 300μg of G-CSF for pre-DC mobilization and a 50-70 mL blood draw 24-48 hours later. Total vaccine production time was 72 hrs. Pts were randomized 2:1 to receive TLPLDC or placebo (DCs exposed to empty YCWPs). 1-1.5 x10^6 cells/dose were injected intradermally at 0, 1, 2, 6, 12, and 18 months. Differences in disease free survival (DFS) and overall survival (OS) were evaluated by Kaplan Meier analysis between pts who did not receive pretreatment (TLPLDC), pts who did receive pretreatment with G-CSF (TLPLDC+G), and pts receiving placebo. RNA-seq analysis was performed on the total RNA of pts’ prepared TLPLDC vaccines to assess gene expression. Relative RNA expression (RRE) was compared between TLPLDC and TLPLDC+G. Results: As previously reported, 144 pts were randomized: 103 received TLPLDC (46 TLPLDC, 57 TLPLDC+G) and 41 received placebo. There were no significant clinicopathologic or treatment differences between the three treatment arms. Survival was significantly improved in TLPLDC compared to TLPLDC+G or placebo, including 36-month OS (92.9% vs 62.8% vs 72.3% respectively, p = 0.022) and DFS (51.8% vs 23.4% vs 27.1%, p = 0.027). When compared to TLPLDC+G (n = 3) vaccine, RNA-seq from TLPLDC vaccine (n = 3) showed upregulation of genes associated with DC maturation, including HLA-DMB (RRE: 3.60), IFIT1 (3.38), CD27 (3.26), IFI44L (3.24), MX1 (2.96), HLA-DQA1 (2.67), HLA-DRA (2.40), CD49D (2.34) and CD74 (2.09), while downregulated genes were associated with DC suppression or immaturity including SERPINA1 (RRE:7.8), TLR2 (6.65), CCR1 (5.11), IL10 (4.19), CD93 (3.84) and CD14 (3.25). Conclusions: Pts receiving TLPLDC vaccine had significantly improved OS and DFS, while outcomes remained similar between those who received TLPLDC+G vs placebo. Pts who did not receive G-CSF had higher expression of genes linked to DC maturation and antigen processing and presentation, likely explaining the improvement in clinical efficacy. A phase III trial to further assess the TLPLDC vaccine to prevent recurrence is planned. Clinical trial information: NCT02301611.

scholarly journals Cross-Presentation of Human Cytomegalovirus pp65 (UL83) to CD8+ T Cells Is Regulated by Virus-Induced, Soluble-Mediator-Dependent Maturation of Dendritic Cells

2002 ◽  
Vol 76 (1) ◽  
pp. 142-150 ◽  
Author(s):  
Géraldine Arrode ◽  
Claire Boccaccio ◽  
Jean-Pierre Abastado ◽  
Christian Davrinche
Keyword(s):  
Dendritic Cells ◽  
Human Cytomegalovirus ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Immune Surveillance ◽  
Transforming Growth Factor Β1 ◽  
Cell Mediated Immunity ◽  
Cross Presentation ◽  
Infected Cells ◽  
Dc Maturation

ABSTRACT Cytotoxic CD8+ T lymphocytes (CTL) directed against the matrix protein pp65 are major effectors in controlling infection against human cytomegalovirus (HCMV), a persistent virus of the Betaherpesvirus family. We previously suggested that cross-presentation of pp65 by nonpermissive dendritic cells (DCs) could overcome viral strategies that interfere with activation of CTL (G. Arrode, C. Boccaccio, J. Lule, S. Allart, N. Moinard, J. Abastado, A. Alam, and C. Davrinche, J. Virol. 74:10018–10024, 2000). It is well established that mature DCs are very potent in initiating T-cell-mediated immunity. Consequently, the DC maturation process is a key step targeted by viruses in order to avoid an immune response. Here, we report that immature DCs maintained in coculture with infected human (MRC5) fibroblasts acquired pp65 from early-infected cells for cross-presentation to specific HLA-A2-restricted CTL. In contrast, coculture of DCs in the presence of late-infected cells decreased their capacity to stimulate CTL. Analyses of DC maturation after either coculture with infected MRC5 cells or incubation with infected-cell-conditioned medium revealed that acquisition of a mature phenotype was a prerequisite for efficient stimulation of CTL and that soluble factors secreted by infected cells were responsible for both up and down regulation of CD83 expression on DCs. We identified transforming growth factor β1 secreted by late HCMV-infected cells as one of these down regulating mediators. These findings suggest that HCMV has devised another means to compromise immune surveillance mechanisms. Together, our data indicate that recognition of HCMV-infected cells by DCs has to occur early after infection to avoid immune evasion and to allow generation of anti-HCMV CTL.

scholarly journals Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells

Blood ◽  
2012 ◽  
Vol 120 (26) ◽  
pp. 5163-5172 ◽  
Author(s):  
Thijs W. H. Flinsenberg ◽  
Ewoud B. Compeer ◽  
Dan Koning ◽  
Mark Klein ◽  
Femke J. Amelung ◽  
...  
Keyword(s):  
Cd8 T Cells ◽  
Lymphoid Tissue ◽  
Antigen Processing ◽  
Cd8 T Cell ◽  
Fcγ Receptor ◽  
Antigen Uptake ◽  
Fcgamma Receptor ◽  
Cross Presentation ◽  
Cell Clones ◽  
Dc Maturation

Abstract The reactivation of human cytomegalovirus (HCMV) poses a serious health threat to immune compromised individuals. As a treatment strategy, dendritic cell (DC) vaccination trials are ongoing. Recent work suggests that BDCA-3+ (CD141+) subset DCs may be particularly effective in DC vaccination trials. BDCA-3+ DCs had however been mostly characterized for their ability to cross-present antigen from necrotic cells. We here describe our study of human BDCA-3+ DCs in elicitation of HCMV-specific CD8+ T-cell clones. We show that Fcgamma-receptor (FcγR) antigen targeting facilitates antigen cross-presentation in several DC subsets, including BDCA-3+ DCs. FcγR antigen targeting stimulates antigen uptake by BDCA-1+ rather than BDCA-3+ DCs. Conversely, BDCA-3+ DCs and not BDCA-1+ DCs show improved cross-presentation by FcγR targeting, as measured by induced release of IFNγ and TNF by antigen-specific CD8+ T cells. FcγR-facilitated cross-presentation requires antigen processing in both an acidic endosomal compartment and by the proteasome, and did not induce substantial DC maturation. FcγRII is the most abundantly expressed FcγR on both BDCA-1+ and BDCA-3+ DCs. Furthermore we show that BDCA-3+ DCs express relatively more stimulatory FcγRIIa than inhibitory FcγRIIb in comparison with BDCA-1+ DCs. These studies support the exploration of FcγR antigen targeting to BDCA-3+ DCs for human vaccination purposes.

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