scholarly journals Oncolytic Viruses As Immunotherapeutic Agents for the Treatment of Malignant Tumors

2019 ◽  
Vol 74 (2) ◽  
pp. 108-117
Author(s):  
Alexander I. Glukhov ◽  
Dmitry A. Sivokhin ◽  
Daria A. Seryak ◽  
Tatyana S. Rodionova ◽  
Margarita I. Kamynina
Keyword(s):  
Cell Death ◽  
Antitumor Immunity ◽  
Randomized Clinical Trials ◽  
Tumor Antigens ◽  
Malignant Tumors ◽  
Oncolytic Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Gm Csf ◽  
Cancer Cell Death

Oncolytic viruses (OVs) are novel and rapidly developing class of therapeutic agents for combating cancer, which can effectively infect and destroy tumor cells, leaving healthy tissues intact. Many viruses have a natural antitumor activity which causes cytolysis of cancer cells due to direct pathogenic action. Along with non-immunogenic cell death, oncolytic viruses have been shown to be capable of inducing immunogenic cancer cell death (necrosis, pyroptosis, etc.) accompanied by the release of OV-lysed tumor-associated antigens (TAAs). Releasing DAMPs and TAAs, in its turn, leads to the activation of adaptive antitumor immunity. In order to further enhance the antitumor immunity, OVs have been armed with immunostimulatory transgenes such as granulocyte-macrophage colony-stimulating factor (GM-CSF), type I interferons, interleukins (IL-2, 12, 15), costimulatory ligands (CD40, CD80), tumor antigens («prime-boost» vaccination), which further enhances the safety and effectiveness of oncolytic virotherapy. Preliminary results of randomized clinical trials of different approaches of oncolytic virotherapies in combination with immunotherapy confirm their high efficacy. However, there are some drawbacks, which necessitates their further study.

scholarly journals Oncolytic Viruses and Cancer, Do You Know the Main Mechanism?

2021 ◽  
Vol 11 ◽  
Author(s):  
Wesam Kooti ◽  
Hadi Esmaeili Gouvarchin Ghaleh ◽  
Mahdieh Farzanehpour ◽  
Ruhollah Dorostkar ◽  
Bahman Jalali Kondori ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Antitumor Immunity ◽  
Malignant Tumors ◽  
Mechanisms Of Action ◽  
Oncolytic Viruses ◽  
Global Rate ◽  
Recent Developments ◽  
Review Study

The global rate of cancer has increased in recent years, and cancer is still a threat to human health. Recent developments in cancer treatment have yielded the understanding that viruses have a high potential in cancer treatment. Using oncolytic viruses (OVs) is a promising approach in the treatment of malignant tumors. OVs can achieve their targeted treatment effects through selective cell death and induction of specific antitumor immunity. Targeting tumors and the mechanism for killing cancer cells are among the critical roles of OVs. Therefore, evaluating OVs and understanding their precise mechanisms of action can be beneficial in cancer therapy. This review study aimed to evaluate OVs and the mechanisms of their effects on cancer cells.

scholarly journals Activation of the MDA-5–IPS-1 Viral Sensing Pathway Induces Cancer Cell Death and Type I IFN-Dependent Antitumor Immunity

2016 ◽  
Vol 76 (8) ◽  
pp. 2166-2176 ◽  
Author(s):  
Xiaofei Yu ◽  
Hongxia Wang ◽  
Xia Li ◽  
Chunqing Guo ◽  
Fang Yuan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Antitumor Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Cancer Cell Death

scholarly journals Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

scholarly journals The STING1 network regulates autophagy and cell death

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruoxi Zhang ◽  
Rui Kang ◽  
Daolin Tang
Keyword(s):  
Cell Death ◽  
Mitotic Cell ◽  
Therapeutic Interventions ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Autophagic Degradation ◽  
Health And Disease ◽  
Shed Light ◽  
Pro Inflammatory Cytokines

AbstractCell death and immune response are at the core of life. In past decades, the endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in the production of type I interferons (IFNs) and pro-inflammatory cytokines in response to DNA derived from invading microbial pathogens or damaged hosts by activating multiple transcription factors. In addition to this well-known function in infection, inflammation, and immunity, emerging evidence suggests that the STING1-dependent signaling network is implicated in health and disease by regulating autophagic degradation or various cell death modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death [ICD]). Here, we outline the latest advances in our understanding of the regulating mechanisms and signaling pathways of STING1 in autophagy and cell death, which may shed light on new targets for therapeutic interventions.

scholarly journals Multi-Immune Agonist Nanoparticle Therapy Stimulates Type I Interferons to Activate Antigen-Presenting Cells and Induce Antigen-Specific Antitumor Immunity

2021 ◽  
Vol 18 (3) ◽  
pp. 1014-1025
Author(s):  
Elizabeth S. Levy ◽  
Ryan Chang ◽  
Colin R. Zamecnik ◽  
Miqdad O. Dhariwala ◽  
Lawrence Fong ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Antigen Presenting Cells ◽  
Type I Interferons ◽  
Type I ◽  
Antigen Presenting

scholarly journals HIV-Infected Macrophages Are Infected and Killed by the Interferon-Sensitive Rhabdovirus MG1

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Teslin S. Sandstrom ◽  
Nischal Ranganath ◽  
Stephanie C. Burke Schinkel ◽  
Syim Salahuddin ◽  
Oussama Meziane ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Oncolytic Viruses ◽  
Type I Interferons ◽  
Viral Reservoir ◽  
Type I ◽  
Antiviral Signaling ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro-infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4+ T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus—initially developed as a cancer therapy—is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field.

scholarly journals Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

2020 ◽  
Author(s):  
Qingyuan Feng ◽  
Xuzhao Bian ◽  
Xuan Liu ◽  
Ying Wang ◽  
Huiting Zhou ◽  
...  
Keyword(s):  
Cell Death ◽  
Western Blot ◽  
Cancer Cell ◽  
Malignant Tumors ◽  
Mitochondrial Damage ◽  
Arginine Deiminase ◽  
Immunofluorescent Staining ◽  
Apoptosis Pathway ◽  
P53 Expression ◽  
Cancer Cell Death

Abstract Background：Based on its low toxicity, arginine starvation therapy has the potential to treat those malignant tumors that can’t be treated by surgery. Arginine deiminase (ADI) gene is indicated to be an ideal cancer-suppressor gene. ADI expressed in cytosol displays higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000). However, it is still unknown whether cytosolic ADI has the same function mechanism as ADI-PEG20 or other underlying mechanisms in cells.Methods: The interaction of ADI and other protein factors was screened by yeast hybrid, and verified by co-immunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting ferritin light-chain domain (FTL) on mitochondrial damage was evaluated by site-directed mutation and flow cytometry. The apoptosis pathway of mitochondria control was analyzed by Western Blot and real-time PCR experiments. The effect of p53 expression on cancer cell death was assessed by siTP53 transfection. The chromatin autophagy was explored by immunofluorescent staining and Western Blot.Results: ADI expressed in cytosol inhibited the activity of cytosolic ferritin through interacting with FTL. The inactive mutant of ADI still induced the apoptosis in certain cell lines of ASS- through mitochondrial damage. Arginine starvation also induced the increased expression of p53 and p53AIP1, which aggravate cellular mitochondrial damage. Chromatin autophagy appeared at the later stage of arginine starvation. DNA damage came along with the whole process of arginine starvation. Histone 3 (H3) was found in autophagosomes, which implied that cancer cells try to utilize the arginine in histones to survive during arginine starvation. Conclusions: Mitochondrial damage is the major mechanism of cell death induced by cytosolic ADI. Chromatophagy accumulations not only drive cancer cell to utilize histone arginine but also speed up cancer cell death at the later time point of arginine starvation.

scholarly journals Janus Kinase-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Lucas Walz ◽  
Avi J. Cohen ◽  
Andre P. Rebaza ◽  
James Vanchieri ◽  
Martin D. Slade ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Outcomes ◽  
Randomized Clinical Trials ◽  
Type I Interferon ◽  
Meta Analysis ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Jak Inhibitor ◽  
Jak Inhibitors

Background Novel coronavirus (SARS-CoV-2) has infected over 17 million. Novel therapies are urgently needed. Janus-kinase (JAK) inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and by their ability to promote viral clearance in past coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate role of these therapies in COVID-19 patients. Methods MEDLINE and MedRxiv were searched until July 30th, 2020, including studies that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clear risk estimates or those that permitted back-calculation. Results We searched 733 studies, ultimately including four randomized and eleven non-randomized clinical trials. JAK-inhibitor recipients had significantly reduced odds of mortality (OR, 0.12; 95%CI, 0.03-0.39, p=0.0005) and ICU admission (OR, 0.05; 95%CI, 0.01-0.26, p=0.0005), and had significantly increased odds of hospital discharge (OR, 22.76; 95%CI, 10.68-48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95%CI, 0.04-0.85, p=0.03), and increased odds of discharge bordering significance (OR, 1.89; 95%CI, 1.00-3.59, p=0.05). Conclusions JAK-inhibitor treatment is significantly associated with positive clinical outcomes regarding mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes regarding mortality and discharge. While these data show promise, additional randomized clinical trials are needed to further elucidate the efficacy of JAK-inhibitors and Type I interferons and clinical outcomes in COVID-19.

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