Parvovirus H-1-Induced Tumor Cell Death Enhances Human Immune Response In Vitro via Increased Phagocytosis, Maturation, and Cross-Presentation by Dendritic Cells

2005 ◽  
Vol 0 (0) ◽  
pp. 050701034702004
Author(s):  
Markus H. Moehler ◽  
Maja Zeidler ◽  
Vanessa Wilsberg ◽  
Jan J. Cornelis ◽  
Thomas Woelfel ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cell Death ◽  
Cross Presentation ◽  
Human Immune Response ◽  
Human Immune ◽  
Immune Response In Vitro

Parvovirus H-1-Induced Tumor Cell Death Enhances Human Immune Response In Vitro via Increased Phagocytosis, Maturation, and Cross-Presentation by Dendritic Cells

2005 ◽  
Vol 0 (0) ◽  
pp. 050719131035001
Author(s):  
Markus H. Moehler ◽  
Maja Zeidler ◽  
Vanessa Wilsberg ◽  
Jan J. Cornelis ◽  
Thomas Woelfel ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cell Death ◽  
Cross Presentation ◽  
Human Immune Response ◽  
Human Immune ◽  
Immune Response In Vitro

scholarly journals O8 Gemcitabine induces pro-apoptotic BH3 only proteins and sensitizes pancreatic ductal adenocarcinoma cells for RLH-triggered immunogenic cell death

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A7.1-A7
Author(s):  
P Metzger ◽  
HT Bourhis ◽  
M Stieg ◽  
D Böhmer ◽  
S Endres ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Tumor Cell ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Immunogenic Cell Death ◽  
Tumor Cell Death ◽  
Antigen Uptake ◽  
Cross Presentation

BackgroundDespite tremendous effort, the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) remains poor and therapy options are limited. Recent advances in chemotherapeutic schemes have increased the survival of PDAC patients by a few months only. So far, the success of immunotherapy seen in other cancer types could not be transferred to PDAC. Our group has demonstrated that single agent RIG-I-like helicase (RLH)-targeting immunotherapy induces an anti-tumoral immune response and improves survival in a PDAC mouse model dependent on the induction of immunogenic cell death. In addition, we and others were able to show that tumor cell death induction by RLH ligands is partially dependent on the induction of the pro-apoptotic BH3-only proteins PUMA and NOXA. In the current study we aim at improving therapy response using a combinatorial chemo-immunotherapy (CIT) approach.MethodsTumor cell death induction by gemcitabine, oxaliplatin and 5-fluoruracil (5-FU) alone or in combination with RLH ligands was evaluated in the murine cell line Panc02. The induction of PUMA and NOXA was measured by real-time PCR. The capability of chemo-immunotherapy -induced tumor cell death to activate splenic CD8a+dendritic cells (DC) as well as to induce antigen uptake and cross-presentation was investigated in vitro. Therapeutic efficacy was evaluated in vivo using an orthotopic PDAC mouse model.ResultsGemcitabine, oxaliplatin and 5-FU induced dose-dependent tumor cell death in vitro. however, only gemcitabine lead to an induction of the pro-apoptotic proteins PUMA and NOXA. Simultaneous treatment with gemcitabine and RLH-ligand increased cell death induction without affecting the cytokine secretion substantially. CD8a+ DC activation upon RLH-therapy was not affected by chemotherapy. Of note, antigen uptake as well as T cell priming was increased by chemo-immunotherapy. Most importantly, the survival of orthotopic PDAC bearing mice was significantly prolonged in the chemo-immunotherapy group compared to single agent treatment.ConclusionsGemcitabine treatment of PDAC induces PUMA and NOXA expression which leads to mitochondrial priming and sensitization towards RLH-induced cell death. chemo-immunotherapy increases the cross-presentation capability of DC in vitro and prolongs the survival of PDAC bearing mice. chemo-immunotherapy is therefore an attractive combinatorial therapeutic approach in PDAC.FundingThe project was supported by the Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 179062510 and 329628492 - SFB 1321 as well as the Förderprogramm für Forschung und Lehre (FöFoLe) funded by the Ludwig-Maximilians-Universität München.Disclosure InformationP. Metzger: None. H.T. Bourhis: None. M. Stieg: None. D. Böhmer: None. S. Endres: None. P. Düwell: None. L.M. König: None. M. Schnurr: None.

scholarly journals Clostridium difficile toxins A and B inhibit human immune response in vitro.

1988 ◽  
Vol 56 (5) ◽  
pp. 1107-1112 ◽  
Author(s):  
W Däubener ◽  
E Leiser ◽  
C von Eichel-Streiber ◽  
U Hadding
Keyword(s):  
Immune Response ◽  
Clostridium Difficile ◽  
Human Immune Response ◽  
Human Immune ◽  
Immune Response In Vitro

scholarly journals Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death

2005 ◽  
Vol 202 (12) ◽  
pp. 1691-1701 ◽  
Author(s):  
Noelia Casares ◽  
Marie O. Pequignot ◽  
Antoine Tesniere ◽  
François Ghiringhelli ◽  
Stéphan Roux ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Cell Death ◽  
Anticancer Chemotherapy ◽  
Caspase Inhibition ◽  
Induced Apoptosis

Systemic anticancer chemotherapy is immunosuppressive and mostly induces nonimmunogenic tumor cell death. Here, we show that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia. Although both antracyclins and mitomycin C induced apoptosis with caspase activation, only anthracyclin-induced immunogenic cell death was immunogenic. Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia. Depletion of dendritic cells (DCs) or CD8+T cells abolished the immune response against DX-treated apoptotic tumor cells in vivo. Caspase inhibition suppressed the capacity of DX-killed cells to be phagocytosed by DCs, yet had no effect on their capacity to elicit DC maturation. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral inoculation of DX could trigger the regression of established tumors in immunocompetent mice. These results delineate a procedure for the generation of cancer vaccines and the stimulation of anti-neoplastic immune responses in vivo.

scholarly journals Cellular cytotoxicity is a form of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000325 ◽  
Author(s):  
Luna Minute ◽  
Alvaro Teijeira ◽  
Alfonso R Sanchez-Paulete ◽  
Maria C Ochoa ◽  
Maite Alvarez ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Immunogenic Cell Death ◽  
Cell Debris ◽  
Tumor Cell Death ◽  
Mhc Multimer

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.

scholarly journals The Human Immune Response to Respiratory Syncytial Virus Infection

2017 ◽  
Vol 30 (2) ◽  
pp. 481-502 ◽  
Author(s):  
Clark D. Russell ◽  
Stefan A. Unger ◽  
Marc Walton ◽  
Jürgen Schwarze
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
T Cell ◽  
T Cell Response ◽  
Rsv Infection ◽  
Human Immune Response ◽  
Ifn Γ ◽  
Human Immune ◽  
Syncytial Virus

SUMMARY Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

scholarly journals Dominant-negative ATF5 rapidly depletes survivin in tumor cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xiaotian Sun ◽  
James M. Angelastro ◽  
David Merino ◽  
Qing Zhou ◽  
Markus D. Siegelin ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Dominant Negative ◽  
Tumor Cell Death ◽  
Cell Penetrating ◽  
Selective Death ◽  
Tumor Types

Abstract Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid–based proteasome inhibitors

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5927-5937 ◽  
Author(s):  
Encouse B. Golden ◽  
Philip Y. Lam ◽  
Adel Kardosh ◽  
Kevin J. Gaffney ◽  
Enrique Cadenas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Tumor Cell ◽  
Green Tea ◽  
Boronic Acid ◽  
Proteasome Inhibitors ◽  
Green Tea Polyphenols ◽  
Tumor Cell Death

Abstract The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this “miracle herb” in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid–based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non–boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.

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