scholarly journals P. aeruginosa Mediated Necroptosis in Mouse Tumor Cells Induces Long-Lasting Systemic Antitumor Immunity

2021 ◽  
Vol 10 ◽  
Author(s):  
Jia-long Qi ◽  
Jin-rong He ◽  
Shu-mei Jin ◽  
Xu Yang ◽  
Hong-mei Bai ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Response ◽  
Necrotic Cell Death ◽  
Immunogenic Cell Death ◽  
Mouse Tumor ◽  
Necrotic Cell ◽  
Tumor Cell Death

Necroptosis is a form of programmed cell death (PCD) characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What’s more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and local immune microenvironment in tumor. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping tumor microenvironment.

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 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 Repurposing Cationic Amphiphilic Drugs and Derivatives to Engage Lysosomal Cell Death in Cancer Treatment

2020 ◽  
Vol 10 ◽  
Author(s):  
Michelle Hu ◽  
Kermit L. Carraway
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Cellular Transformation ◽  
Therapeutic Window ◽  
Cell Populations ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Membrane Rupture ◽  
Cationic Amphiphilic Drugs ◽  
Amphiphilic Drugs

A major confounding issue in the successful treatment of cancer is the existence of tumor cell populations that resist therapeutic agents and regimens. While tremendous effort has gone into understanding the biochemical mechanisms underlying resistance to each traditional and targeted therapeutic, a broader approach to the problem may emerge from the recognition that existing anti-cancer agents elicit their cytotoxic effects almost exclusively through apoptosis. Considering the myriad mechanisms cancer cells employ to subvert apoptotic death, an attractive alternative approach would leverage programmed necrotic mechanisms to side-step therapeutic resistance to apoptosis-inducing agents. Lysosomal cell death (LCD) is a programmed necrotic cell death mechanism that is engaged upon the compromise of the limiting membrane of the lysosome, a process called lysosomal membrane permeabilization (LMP). The release of lysosomal components into the cytosol upon LMP triggers biochemical cascades that lead to plasma membrane rupture and necrotic cell death. Interestingly, the process of cellular transformation appears to render the limiting lysosomal membranes of tumor cells more fragile than non-transformed cells, offering a potential therapeutic window for drug development. Here we outline the concepts of LMP and LCD, and discuss strategies for the development of agents to engage these processes. Importantly, the potential exists for existing cationic amphiphilic drugs such as antidepressants, antibiotics, antiarrhythmics, and diuretics to be repurposed to engage LCD within therapy-resistant tumor cell populations.

Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells

2010 ◽  
Vol 391 (1) ◽  
pp. 1014-1020 ◽  
Author(s):  
Petra Schildkopf ◽  
Benjamin Frey ◽  
Frederick Mantel ◽  
Oliver J. Ott ◽  
Eva-Maria Weiss ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Colorectal Tumor ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Ionizing Irradiation

Apoptosis and Tumor Cell Death in Response to HAMLET (Human α-Lactalbumin Made Lethal to Tumor Cells)

2007 ◽  
pp. 217-240 ◽  
Author(s):  
Oskar Hallgren ◽  
Sonja Aits ◽  
Patrick Brest ◽  
Lotta Gustafsson ◽  
Ann-Kristin Mossberg ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Cell Death

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 Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1823 ◽  
Author(s):  
Jenny Sprooten ◽  
Pieter De Wijngaert ◽  
Isaure Vanmeerbeek ◽  
Shaun Martin ◽  
Peter Vangheluwe ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Inflammatory Cell ◽  
Necrotic Cell Death ◽  
Immunogenic Cell Death ◽  
Necrotic Cell ◽  
Cell Death Pathway ◽  
Immune Checkpoint Blockers ◽  
Anticancer Immunity

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To “break” cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

Determination of apoptotic and necrotic cell death in vitro and in vivo

Methods ◽  
2013 ◽  
Vol 61 (2) ◽  
pp. 117-129 ◽  
Author(s):  
Tom Vanden Berghe ◽  
Sasker Grootjans ◽  
Vera Goossens ◽  
Yves Dondelinger ◽  
Dmitri V. Krysko ◽  
...  
Keyword(s):  
Cell Death ◽  
Necrotic Cell Death ◽  
Necrotic Cell
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