scholarly journals Astragalus polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2264 ◽  
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Kuang-Tai Kuo ◽  
Chun-Hua Wang ◽  
Wen-Chien Huang ◽  
Alexander T.H. Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Ex Vivo ◽  
M2 Macrophage ◽  
Anticancer Effect ◽  
Inflammatory Cascade ◽  
Functional Maturation

Background: Recently, we demonstrated that Astragalus polysaccharide (PG2), the active ingredient in dried roots of astragalus membranaceus, ameliorates cancer symptom clusters and improves quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade against the background roles of inflammatory cells, including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear. Purpose: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade and enhances anticancer immunity, as well as the therapeutic implication of these bio-events in patients with lung cancer. Methods and Results: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity, and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that treatment with PG2 elicited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibited xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscrasia and weight-loss was markedly suppressed. Conclusion: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin, thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.

scholarly journals Astragalus Polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer

2019 ◽  
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Kuang-Tai Kuo ◽  
Chun-Hua Wang ◽  
Wen-Chien Huang ◽  
Alexander T.H. Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Ex Vivo ◽  
M2 Macrophage ◽  
Anticancer Effect ◽  
Inflammatory Cascade ◽  
Functional Maturation

Background: Recently we demonstrated that Astragalus polysaccharide (PG2), the active ingredient in dried roots of astragalus membranaceus, ameliorates cancer symptom clusters and improve quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade, against the background that inflammatory cells including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear. Purpose: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade, enhance anticancer immunity, and the therapeutic implication of same in patients with lung cancer. Methods and Results: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro, positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that mice treated with PG2 exhibited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibition of xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscresia and weight-loss was markedly suppressed. Conclusion: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation, and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin; thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.

scholarly journals CD14 Expressing Precursors Give Rise to Highly Functional Conventional Dendritic Cells for Use as Dendritic Cell Vaccine

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3818
Author(s):  
Maud Plantinga ◽  
Denise A. M. H. van den Beemt ◽  
Ester Dünnebach ◽  
Stefan Nierkens
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cord Blood ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Activated T Cells

Induction of long-lasting immunity by dendritic cells (DCs) makes them attractive candidates for anti-tumor vaccination. Although DC vaccinations are generally considered safe, clinical responses remain inconsistent in clinical trials. This initiated studies to identify subsets of DCs with superior capabilities to induce effective and memory anti-tumor responses. The use of primary DCs has been suggested to overcome the functional limitations of ex vivo monocyte-derived DCs (moDC). The ontogeny of primary DCs has recently been revised by the introduction of DC3, which phenotypically resembles conventional (c)DC2 as well as moDC. Previously, we developed a protocol to generate cDC2s from cord blood (CB)-derived stem cells via a CD115-expressing precursor. Here, we performed index sorting and single-cell RNA-sequencing to define the heterogeneity of in vitro developed DC precursors and identified CD14+CD115+ expressing cells that develop into CD1c++DCs and the remainder cells brought about CD123+DCs, as well as assessed their potency. The maturation status and T-cell activation potential were assessed using flow cytometry. CD123+DCs were specifically prone to take up antigens but only modestly activated T-cells. In contrast, CD1c++ are highly mature and specialized in both naïve as well as antigen-experienced T-cell activation. These findings show in vitro functional diversity between cord blood stem cell-derived CD123+DC and CD1c++DCs and may advance the efficiency of DC-based vaccines.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

Abstract We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

scholarly journals Dendritic cells transduced by multiply deleted HIV-1 vectors exhibit normal phenotypes and functions and elicit an HIV-specific cytotoxic T-lymphocyte response in vitro

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1327-1333 ◽  
Author(s):  
Andreas Gruber ◽  
June Kan-Mitchell ◽  
Kelli L. Kuhen ◽  
Tetsu Mukai ◽  
Flossie Wong-Staal
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Response ◽  
Adoptive T Cell Therapy ◽  
Cytotoxic T Cell ◽  
T Cell Therapy ◽  
Hiv 1

Abstract Dendritic cells (DCs) genetically modified to continually express and present antigens may be potent physiologic adjuvants for induction of prophylactic or therapeutic immunity. We have previously shown that an env and nef deleted HIV-1 vector (HIV-1ΔEN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34+ precursors of DCs. Here we extended these findings with HIV-1ΔEN to highly differentiated human DCs derived in culture from circulating monocytes (DCs). In addition, a new vector derived from HIV-1ΔEN but further deleted in its remaining accessory genes vif, vpr, and vpu(HIV-1ΔEN V3) was also tested. Both vectors efficiently transduced DCs. Transduction of DCs did not significantly alter their viability or their immunophenotype when compared with untransduced DCs. Furthermore, the phagocytic potential of immature DCs, as well as their ability to differentiate into mature DCs capable of stimulating T-cell proliferation, was not affected. Finally, DCs transduced by the HIV-1ΔEN vector were able to elicit a primary antiviral cytotoxic T-cell response in autologous CD8 T cells. These results suggest that HIV-1–based vectors expressing viral antigens may be useful for in vivo active immunization as well as ex vivo priming of cytotoxic T cells for adoptive T-cell therapy.

Generation of Regulatory T Cells through Intravenous Delivery of Autologous Apoptotic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2390-2390
Author(s):  
David Peritt ◽  
Kim Campbell ◽  
Amy Krutsick ◽  
Janine Huber ◽  
Ulrich Thienel ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Ex Vivo ◽  
Contact Hypersensitivity ◽  
Phase Iii ◽  
Apoptotic Cells ◽  
Phase Ii Trials

Abstract Extracorporeal photopheresis (ECP) is approved for the palliative treatment of skin manifestations associated with cutaneous T cell lymphoma. As reported in the literature, ECP has shown promise as a treatment for such immune-mediated inflammatory disorders as graft versus host disease, transplantation rejection, and autoimmune diseases. ECP involves the reinfusion of autologous, apoptotic peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen (8-MOP) and UVA light. The biological mechanism of action of ECP, however, remains unresolved. We have evidence to suggest that delivery of ECP-treated apoptotic cells modulates immune responses, possibly through generation of regulatory T cells. When co-incubated with ECP-treated cells, activated dendritic cells produce reduced levels of proinflammatory cytokines, such as IL-12, while TGFβ levels were modestly increased. Activation of CD4+ T cells in the presence of allogeneic dendritic cells and ECP-treated cells promotes generation of a population of T cells that can suppress proliferation of, and IFNγ production by, naïve syngeneic T cells. To confirm these findings in vivo, we employed a murine contact hypersensitivity model. ECP-treated or control spleen and lymph node cells from mice sensitized with the hapten dinitrofluorobenzene (DNFB) were injected intravenously into naïve recipients. Compared to controls, mice that received ECP-treated cells demonstrated significantly less ear swelling following sensitization and challenge with DNFB. Suppression of ear swelling was specific for DNFB and cell-mediated, as demonstrated by the ability to transfer DNFB tolerance to naïve mice, which could appropriately respond to the unrelated hapten oxazalone. Transfer of this tolerance was abrogated by depletion of either CD4+ or CD25+ T cell populations. Collectively, these results suggest that delivery of ECP-treated cells promotes the generation of regulatory T cells that are capable of modulating immune responses. Therakos sponsored Phase II trials for the prevention and treatment of GvHD are concluding and an international blinded pivotal phase III study is planned for 2005.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

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.

scholarly journals SLC gene-modified dendritic cells mediate T cell-dependent anti-gastric cancer immune responses in vitro

2012 ◽  
Vol 29 (2) ◽  
pp. 595-604 ◽  
Author(s):  
GANG XUE ◽  
YING CHENG ◽  
FENG RAN ◽  
XIANHUI LI ◽  
TAO HUANG ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses

scholarly journals Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

2022 ◽  
Vol 12 ◽  
Author(s):  
Valentina Ceglia ◽  
Sandra Zurawski ◽  
Monica Montes ◽  
Mitchell Kroll ◽  
Aurélie Bouteau ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Class I ◽  
Agonist Activity ◽  
Cell Immunity ◽  
Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

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