An aminophosphonate ester ligand-containing platinum(ii) complex induces potent immunogenic cell death in vitro and elicits effective anti-tumour immune responses in vivo

2019 ◽  
Vol 55 (87) ◽  
pp. 13066-13069 ◽  
Author(s):  
Ke-Bin Huang ◽  
Feng-Yang Wang ◽  
Hai-Wen Feng ◽  
Hejiang Luo ◽  
Yan Long ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Immunogenic Cell Death

A platinum(ii)-aminophosphonate complex (Pt1) induces potent anti-tumour immunogenic cell death (ICD) in vitro and in vivo.

scholarly journals Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2423-2440 ◽  
Author(s):  
Canyu Yang ◽  
Bing He ◽  
Qiang Zheng ◽  
Dakuan Wang ◽  
Mengmeng Qin ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Tumor Burden ◽  
Antitumor Efficacy ◽  
In Vivo Studies ◽  
Immunogenic Cell Death ◽  
Indoleamine 2,3 Dioxygenase ◽  
Tumor Tissues

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

scholarly journals Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000337 ◽  
Author(s):  
Lorenzo Galluzzi ◽  
Ilio Vitale ◽  
Sarah Warren ◽  
Sandy Adjemian ◽  
Patrizia Agostinis ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Adaptive Immune Response ◽  
Operational Definition ◽  
Immunogenic Cell Death ◽  
Adaptive Immune ◽  
Regulated Cell Death ◽  
Definition Of

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

scholarly journals P06.01 Delta24-ACT oncolytic adenovirus as a therapeutic approach for DIPG

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii36-iii36
Author(s):  
V Laspidea ◽  
M Puigdelloses ◽  
M García-Moure ◽  
I Iñigo-Marco ◽  
J Gallego ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Death ◽  
Cell Lines ◽  
In Vivo Studies ◽  
Immunogenic Cell Death ◽  
Murine Models ◽  
Antitumoral Effect ◽  
Infected Cells

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor, being the leading cause of pediatric death caused by cancer. We previously showed that administration of the oncolytic virus Delta-24-RGD to DIPG murine models was safe and led to an increase in the median survival of these animals. However, not all the animals responded, underscoring the need to improve this therapy. In order to increase the antitumoral effect of the virus, we have engineered Delta-24-RGD with the costimulatory ligand 4-1BBL (Delta24-ACT). 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. In this project, we evaluated the oncolytic effect of Delta24-ACT and the antitumor immune response in DIPG murine models. MATERIALS AND METHODS We use the NP53 and XFM murine DIPG cell lines. Flow cytometry was used to assess cell infectivity and ligand expression. We analyzed viral replication using a method based in hexon detection, and viral cytotoxic effect using the MTS assay. For immunogenic cell death analysis, we measured ATP secretion by a luminometric assay and calreticulin location by flow cytometry and immunofluorescence. For in vivo studies, cells and virus were injected in the pons of the mice, using the screw-guided system. RESULTS In vitro, Delta24-ACT was able to infect and induce cell death in a dose-dependent manner in murine DIPG cell lines. In addition, Delta24-ACT was able to replicate in these tumor cells and to express viral proteins. Moreover, infected cells expressed 41BBL in their membranes. Delta24-ACT could induce immunogenic cell death due to an increased secretion of ATP and calreticulin translocation to the membrane of infected cells (in no-infected cells it located in the ER), DAMPs that can trigger the immune response activation. In vivo, Delta24-ACT demonstrated to be safe in all the tested doses and was able to induce a significant increase in the median survival of the treated animals. Moreover, long-term survivors display immunological memory. CONCLUSIONS Delta24-ACT treatment led to antitumoral effect in DIPG murine cell lines in vitro. Of significance, we have demonstrated that in vivo administration of Delta24-ACT is safe and results in an enhanced antitumor effect. Future in vivo studies will explore the underlying immune mechanism of the virus.

scholarly journals Combining the IAP Antagonist Tolinapant with a DNA Hypomethylating Agent Enhances Immunogenic Cell Death in Preclinical Models of T-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3986-3986
Author(s):  
George A. Ward ◽  
Simone Jueliger ◽  
Martin Sims ◽  
Matthew Davis ◽  
Adam Boxall ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cell Lines ◽  
Western Blotting ◽  
Inflammatory Mediators ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Immunogenic Cell Death

Abstract Introduction: Tolinapant is a potent, non-peptidomimetic antagonist of cIAP1, cIAP2 and XIAP. In ongoing Phase 2 trial (NCT02503423), tolinapant has shown activity against highly pre-treated peripheral and cutaneous T-cell lymphoma (Samaniego et al., Hematological Oncology, 2019). Hypomethylating agents (HMAs) have also shown clinical responses in some subsets of PTCL (Lemonnier et al., Blood, 2019). Both HMAs and IAP antagonists show immunomodulatory anti-cancer potential in pre-clinical studies. A Phase 1 clinical study investigating the combination of tolinapant and ASTX727 (oral decitabine) in AML is currently in progress (NCT04155580). Here we have undertaken a biomarker-driven approach to understand the potential for induction of immunogenic forms of cell death (ICD), such as necroptosis, by rational combination of our clinical compounds in pre-clinical models of T-cell lymphoma (TCL). Methods: On-target effects of decitabine and tolinapant were measured by analysing levels of DNMT1 and cIAP1, respectively, by Western blotting in mouse and human cell lines. Levels of key apoptosis, necroptosis or pyroptosis biomarkers were also monitored by Western blotting to provide evidence of lytic cell death contributing to a potential immune response. RIPK3- or MLKL-knockout cell lines were generated by CRISPR to demonstrate involvement of necroptosis in drug-induced cell death in a T-cell lymphoma cell line (BW5147.G.1.4) in vitro. Cell death was monitored by viability (CellTiterGlo) or real-time microscopy (IncuCyte) assays. Levels of key inflammatory mediators or DAMPS were measured in tissue culture supernatants and mouse plasma by Luminex assay (Ampersand). Results: Combined treatment of tolinapant and decitabine led to depletion of cIAP1 and DNMT1 in TCL cell lines, demonstrating on-target activity of tolinapant and decitabine, respectively. The combination of tolinapant and decitabine acted synergistically in mouse and human T-cell lymphoma cell lines to reduce viability in proliferation assays. Necroptosis was induced by decitabine or tolinapant alone in mouse TCL cell lines with robust activation of the RIPK1/RIPK3/MLKL necroptosis pathway when caspase activity was inhibited, and the combination of both agents enhanced loss of viability. Furthermore, we demonstrated decitabine treatment led to re-expression of both RIPK3 and MLKL in mouse cell lines, supporting published evidence that methylation can silence these key biomarkers (Koo et al., Cell Research, 2015; Koch et al., Neoplasia, 2021). Enhanced release of chemokine, cytokine and DAMPs was demonstrated with the combination of agents in vitro and in vivo. By removal of key necroptosis pathway components using CRISPR, we confirmed the importance of this lytic cell death pathway by demonstrating that RIPK3 -/- and MLKL -/- T-cell lymphoma (BW5147.G.1.4) cell lines had reduced necroptosis potential after treatment with tolinapant or decitabine alone or in combination; and demonstrate reduced release of inflammatory mediators in vitro. Finally, our in vivo evaluation of the combination of agents in mouse syngeneic models suggested that increased anti-tumour activity and immune-potentiating systemic biomarker modulation can be achieved with a tolerated dosing regimen of both compounds. Conclusion: These data demonstrate that decitabine enhances immunogenic cell death induced by tolinapant through the re-expression of genes in the necroptotic pathway. This finding provides strong rationale to explore this combination clinically. Disclosures Sims: Astex Pharmaceuticals: Current Employment. Davis: Astex Pharmacueticals: Current Employment. Smyth: Astex Pharmaceuticals: Current Employment.

scholarly journals ID:3005 Combination of vaccine-strain measles and mumps viruses enhances oncolytic activity against human solid malignancies: special focus on prostate cancer

2017 ◽  
Vol 4 (S) ◽  
pp. 17
Author(s):  
Toan Linh Nguyen ◽  
Ho Anh Son ◽  
LiFeng Zhang ◽  
Bui Khac Cuong ◽  
Hoang Van Tong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Therapeutic Option ◽  
Oncolytic Viruses ◽  
Special Focus ◽  
Immunogenic Cell Death ◽  
Solid Malignancies ◽  
Anti Tumor Activity

Oncolytic viruses (OLVs) including measles and mumps viruses (MeV and MuV) have a potential to serve as a therapeutic option for cancers. We have previously shown that the combination of MeV and MuV synergistically kills various human haematological cancer cells. This study aims to investigate the anti-tumor activity of MeV, MuV and MeV-MuV combination (MM) against human solid malignancies in vitro and in vivo. The results showed that MeV, MuV and MM combination targeted and effectively killed various cancer cell lines of human solid malignancies but not normal cells. Notably, MM combination demonstrated a greater anti-tumor effect and prolonged survival in a human prostate cancer (PC3) xenograft tumour model compared to MeV and MuV. MeV, MuV and MM combination significantly induced the expression of immunogenic cell death (ICD) markers and enhanced spleen-infiltrating immune cells such as macrophages, natural killer and dendritic cells. Our study demonstrated that MM combination is a promising option for treatment of human solid malignancies and suggested that MM could induce immunogenic cell death of malignant cells and activate immunity against cancers.

scholarly journals 456 Bortezomib induces immunogenic cell death in melanoma and enhances immune responses in vivo

2019 ◽  
Vol 139 (9) ◽  
pp. S293
Author(s):  
S.M. Daignault ◽  
R.J. Ju ◽  
L. Spoerri ◽  
S.J. Stehbens ◽  
R. Dolcetti ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Immunogenic Cell Death

scholarly journals Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity

2020 ◽  
Vol 8 (2) ◽  
pp. e001369 ◽  
Author(s):  
Iuliia Efimova ◽  
Elena Catanzaro ◽  
Louis Van der Meeren ◽  
Victoria D Turubanova ◽  
Hamida Hammad ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Antitumor Immunity ◽  
High Mobility ◽  
Adaptive Immune System ◽  
Immunogenic Cell Death ◽  
Term Survival ◽  
Atomic Force

BackgroundImmunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown.MethodsFerroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c+CD86+, CD11c+CD40+, CD11c+MHCII+, IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2−/−) mice was used to analyze ferroptosis immunogenicity.ResultsFerroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors’ analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2−/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells.ConclusionsThese results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy.

scholarly journals Novel porphyrazine-based photodynamic anti-cancer therapy induces immunogenic cell death

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Victoria D. Turubanova ◽  
Tatiana A. Mishchenko ◽  
Irina V. Balalaeva ◽  
Iuliia Efimova ◽  
Nina N. Peskova ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Adaptive Immune System ◽  
Immunogenic Cell Death ◽  
Immunodeficient Mice ◽  
Anti Cancer ◽  
Molecular Patterns

AbstractThe immunogenicity of dying cancer cells determines the efficacy of anti-cancer therapy. Photodynamic therapy (PDT) can induce immunogenic cell death (ICD), which is characterized by the emission of damage-associated molecular patterns (DAMPs) from dying cells. This emission can trigger effective anti-tumor immunity. Only a few photosensitizers are known to induce ICD and, therefore, there is a need for development of new photosensitizers that can induce ICD. The purpose of this work was to analyze whether photosensitizers developed in-house from porphyrazines (pz I and pz III) can induce ICD in vitro and in vivo when used in PDT. We indetified the optimal concentrations of the photosensitizers and found that, at a light dose of 20 J/cm2 (λex 615–635 nm), both pz I and pz III efficiently induced cell death in cancer cells. We demonstrate that pz I localized predominantly in the Golgi apparatus and lysosomes while pz III in the endoplasmic reticulum and lysosomes. The cell death induced by pz I-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) but not by ferrostatin-1 and DFO (ferroptosis inhibitors) or by necrostatin-1 s (necroptosis inhibitor). By contrast, the cell death induced by pz III-PDT was inhibited by z-VAD-fmk and by the necroptosis inhibitor, necrostatin-1 s. Cancer cells induced by pz I-PDT or pz III-PDT released HMGB1 and ATP and were engulfed by bone marrow-derived dendritic cells, which then matured and became activated in vitro. We demonstrate that cancer cells, after induction of cell death by pz I-PDT or pz III-PDT, are protective when used in the mouse model of prophylactic tumor vaccination. By vaccinating immunodeficient mice, we prove the role of the adaptive immune system in protecting against tumours. All together, we have shown that two novel porphyrazines developed in-house are potent ICD inducers that could be effectively applied in PDT of cancer.

scholarly journals Anticancer Activity of Biogenic Selenium Nanoparticles: Apoptotic and Immunogenic Cell Death Markers in Colon Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5335
Author(s):  
Katerina Spyridopoulou ◽  
Georgios Aindelis ◽  
Aglaia Pappa ◽  
Katerina Chlichlia
Keyword(s):  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Probiotic Strain ◽  
Selenium Nanoparticles ◽  
Immunogenic Cell Death ◽  
Colon Cancer Cells

Colorectal cancer is a health problem with high mortality rates and prevalence. Thus, innovative treatment approaches need to be developed. Biogenic nanoparticles are nanomaterials that can be synthesised in biological systems and, compared to chemically synthesised nanoparticles, have better bioavailability while being more cost-effective, eco-friendlier, and less toxic. In our previous studies, the probiotic strain Lactobacillus casei ATCC 393 was used to synthesise selenium nanoparticles (SeNps), which were shown to inhibit colon cancer cell growth in vitro and in vivo. Herein, we have further investigated SeNps’ pro-apoptotic activity and their ability to induce immunogenic cell death (ICD) in colon cancer cells. The SeNps’ effect on Caco-2 cells growth was examined along with their potential to induce caspase activation. Moreover, the expression of typical pro-apoptotic and ICD markers were examined in SeNps-treated HT29 and CT26 cells by flow cytometry, Western blot, ELISA and fluorescence microscopy. Elevated caspase-3 activation and surface phosphatyldoserine, that subsided upon co-incubation with a pan-caspase inhibitor, were detected in SeNps-treated cells. Furthermore, nanoparticles induced modulation of the expression of various apoptosis-related proteins. We also report the detection of biomarkers involved in ICD, namely the translocation of calreticulin and ERp57, the release of HMGB1 and ATP, and the secretion of pro-inflammatory cytokines from SeNps-treated cells. Moreover, RAW246.7 macrophages exhibited a higher rate of phagocytosis against treated CT26 when compared to control cells. Taken together, our findings indicate that treatment with SeNps might be an efficient strategy to destroy tumour cells by inducing apoptotic cell death and triggering immune responses.

scholarly journals Doxorubicin-Loaded PLGA Nanoparticles for Cancer Therapy: Molecular Weight Effect of PLGA in Doxorubicin Release for Controlling Immunogenic Cell Death

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1165
Author(s):  
Yongwhan Choi ◽  
Hong Yeol Yoon ◽  
Jeongrae Kim ◽  
Suah Yang ◽  
Jaewan Lee ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cell Death ◽  
Immune Responses ◽  
Release Kinetics ◽  
Plga Nanoparticles ◽  
Chemotherapeutic Agents ◽  
Immunogenic Cell Death ◽  
Tumor Site ◽  
Living Body

Direct local delivery of immunogenic cell death (ICD) inducers to a tumor site is an attractive approach for leading ICD effectively, due to enabling the concentrated delivery of ICD inducers to the tumor site. Herein, we prepared doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using different molecular weight PLGA (7000 g/mol and 12,000 g/mol), showing different drug release kinetics. The different release kinetics of DOX might differently stimulate a tumor cell-specific immune response by releasing damage-associated molecular patterns (DAMPs), resulting in showing a different antitumor response in the living body. DOX-PLGA7K NPs showed faster DOX release kinetics than DOX-PLGA12K NPs in the physiological condition. DOX-PLGA7K NPs and DOX-PLGA12K NPs were successfully taken up by the CT-26 tumor cells, subsequently showing different DOX localization times at the nucleus. Released DOX successfully lead to cytotoxicity and HMGB1 release in vitro. Although the DOX-PLGA7K NPs and DOX-PLGA12K NPs showed different sustained DOX release kinetics in vitro, tumor growth of the CT-26 tumor was similarly inhibited for 28 days post-direct tumor injection. Furthermore, the immunological memory effect was successfully established by the ICD-based tumor-specific immune responses, including DC maturation and tumor infiltration of cytotoxic T lymphocytes (CTLs). We expect that the controlled release of ICD-inducible chemotherapeutic agents, using different types of nanomedicines, can provide potential in precision cancer immunotherapy by controlling the tumor-specific immune responses, thus improving the therapeutic efficacy.

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