Commentary on “A Vaccine for Photodynamic Immunogenic Cell Death: Tumor Cell Caged b y Cellular Disulfide–Thiol Exchange for Immunotherapy”

Tumor cells, caged by the protein shell, are mediated to an immunogenic cell death and transformed into a hot cell vaccine. Such vaccine protects 75% pre-immunized mice against tumor initiation and significantly retards the established tumor growth.

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Cellular cytotoxicity is a form of immunogenic cell death

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000325 ◽

Cited By ~ 3

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.

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.13 ◽

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.

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Graphene-Induced Hyperthermia (GIHT) Combined With Radiotherapy Fosters Immunogenic Cell Death

Frontiers in Oncology ◽

10.3389/fonc.2021.664615 ◽

2021 ◽

Vol 11 ◽

Author(s):

Malgorzata J. Podolska ◽

Xiaomei Shan ◽

Christina Janko ◽

Rabah Boukherroub ◽

Udo S. Gaipl ◽

...

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Cancer Cells ◽

Combined Treatment ◽

Infrared Light ◽

Immunogenic Cell Death ◽

Tumor Cell Death ◽

Induced Hyperthermia ◽

B16f10 Cells ◽

Melanoma B16f10

Radiotherapy and chemotherapy are the standard interventions for cancer patients, although cancer cells often develop radio- and/or chemoresistance. Hyperthermia reduces tumor resistance and induces immune responses resulting in a better prognosis. We have previously described a method to induce tumor cell death by local hyperthermia employing pegylated reduced graphene oxide nanosheets and near infrared light (graphene-induced hyperthermia, GIHT). The spatiotemporal exposure/release of heat shock proteins (HSP), high group mobility box 1 protein (HMGB1), and adenosine triphosphate (ATP) are reported key inducers of immunogenic cell death (ICD). We hypothesize that GIHT decisively contributes to induce ICD in irradiated melanoma B16F10 cells, especially in combination with radiotherapy. Therefore, we investigated the immunogenicity of GIHT alone or in combination with radiotherapy in melanoma B16F10 cells. Tumor cell death in vitro revealed features of apoptosis that is progressing fast into secondary necrosis. Both HSP70 and HMGB1/DNA complexes were detected 18 hours post GIHT treatment, whereas the simultaneous release of ATP and HMGB1/DNA was observed only 24 hours post combined treatment. We further confirmed the adjuvant potential of these released DAMPs by immunization/challenge experiments. The inoculation of supernatants of cells exposed to sole GIHT resulted in tumor growth at the site of inoculation. The immunization with cells exposed to sole radiotherapy rather fostered the growth of secondary tumors in vivo. Contrarily, a discreet reduction of secondary tumor volumes was observed in mice immunized with a single dose of cells and supernatants treated with the combination of GIHT and irradiation. We propose the simultaneous release of several DAMPs as a potential mechanism fostering anti-tumor immunity against previously irradiated cancer cells.

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Abstract 2788: VB6-845d tumor cell killing elicits biologic features of immunogenic cell death

10.1158/1538-7445.am2018-2788 ◽

2018 ◽

Author(s):

Rachelle L. Dillon ◽

Shilpa Chooniedass ◽

Arjune Premsukh ◽

Glen C. MacDonald ◽

Jeannick Cizeau ◽

...

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Cell Killing ◽

Immunogenic Cell Death ◽

Tumor Cell Killing

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

Frontiers in Oncology ◽

10.3389/fonc.2020.610651 ◽

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.

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EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells

Cell Death and Disease ◽

10.1038/s41419-019-2042-y ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 10

Author(s):

Vinay Sagar ◽

Rajita Vatapalli ◽

Barbara Lysy ◽

Sahithi Pamarthy ◽

Jonathan F. Anker ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Tumor Cell ◽

Cancer Cells ◽

Glucose Transporter ◽

Cell Metabolism ◽

Immunogenic Cell Death ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Tumor Cell Death

Abstract The EPHB4 receptor is implicated in the development of several epithelial tumors and is a promising therapeutic target, including in prostate tumors in which EPHB4 is overexpressed and promotes tumorigenicity. Here, we show that high expression of EPHB4 correlated with poor survival in prostate cancer patients and EPHB4 inhibition induced cell death in both hormone sensitive and castration-resistant prostate cancer cells. EPHB4 inhibition reduced expression of the glucose transporter, GLUT3, impaired glucose uptake, and reduced cellular ATP levels. This was associated with the activation of endoplasmic reticulum stress and tumor cell death with features of immunogenic cell death (ICD), including phosphorylation of eIF2α, increased cell surface calreticulin levels, and release of HMGB1 and ATP. The changes in tumor cell metabolism after EPHB4 inhibition were associated with MYC downregulation, likely mediated by the SRC/p38 MAPK/4EBP1 signaling cascade, known to impair cap-dependent translation. Together, our study indicates a role for EPHB4 inhibition in the induction of immunogenic cell death with implication for prostate cancer therapy.

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