scholarly journals EZH2 inhibition: a promising strategy to prevent cancer immune editing

Epigenomics ◽  
2020 ◽  
Vol 12 (16) ◽  
pp. 1457-1476
Author(s):  
Ning Kang ◽  
Mark Eccleston ◽  
Pier-Luc Clermont ◽  
Maryam Latarani ◽  
David Kingsley Male ◽  
...  
Keyword(s):  
Immune Escape ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Cancer Immunoediting ◽  
Wide Range ◽  
Evolutionarily Conserved ◽  
Main Driver ◽  
Immunosuppressive Tumor Microenvironment ◽  
Preclinical And Clinical Studies ◽  
Immune Editing

Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells’ immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment.

Immune Checkpoint Regulators: A New Era Toward Promising Cancer Therapy

2020 ◽  
Vol 20 (6) ◽  
pp. 429-460
Author(s):  
Mohammed Shaaban ◽  
Heba Othman ◽  
Takwa Ibrahim ◽  
Mariam Ali ◽  
Mohamed Abdelmoaty ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Historical Background ◽  
New Era ◽  
Cancer Management ◽  
Immunosuppressive Tumor Microenvironment ◽  
Specific Proteins ◽  
Immune Editing

During the last century, our battle against cancer has been inaugurated upon three main approaches; surgery, radiation and chemotherapy. The latest findings on the effectiveness of immunotherapy in cancer management offer a ray of hope after decades of research and studies on the best treatment methods. Immunotherapy has proven effective in the surveillance and destruction of cancer- causing cells, demonstrating its ability to suppress cancer through controlling the wellestablished immune-editing process. Immuno-editing is a process that comprises three principal elements; elimination, equilibrium, and escape, and is paramount to the comprehension of checkpoint inhibition. Cancer cells employ various approaches to evade the elimination step leading to its immune- escape. The escape mechanism encompasses the up-regulation of negative co-signals that block successful activation of cancer-eradicating immune cells, developing cytokine background that favors the immunosuppressive tumor microenvironment (TME), or dropping the expression of tumor- specific proteins known as neo-antigens, therefore reducing the immunogenic activity against cancer cells. Today, checkpoint inhibitors are considered as a primary approach in our fight against cancer. Strategies targeting the inhibitory roles of checkpoint inhibitors have been shown effective against different cancer types and stages, and some already gained the FDA’s approval. This review seeks to comprehensively cover the historical background as well as the most recent updates for the role of immune checkpoint regulators in the maintenance of immune homeostatic balance as well as keeping the tumorigenic cells in check.

Pursuit of the Abscopal Effect

2020 ◽  
Vol 04 (04) ◽  
pp. 369-372
Author(s):  
Paul B. Romesser ◽  
Christopher H. Crane
Keyword(s):  
Tumor Immunology ◽  
Antitumor Immunity ◽  
Clinical Success ◽  
Immune Recognition ◽  
Immune Modulators ◽  
Cancer Subtypes ◽  
The Past ◽  
Tumor Irradiation ◽  
Wide Range ◽  
Tumor Recognition

AbstractEvasion of immune recognition is a hallmark of cancer that facilitates tumorigenesis, maintenance, and progression. Systemic immune activation can incite tumor recognition and stimulate potent antitumor responses. While the concept of antitumor immunity is not new, there is renewed interest in tumor immunology given the clinical success of immune modulators in a wide range of cancer subtypes over the past decade. One particularly interesting, yet exceedingly rare phenomenon, is the abscopal response, characterized by a potent systemic antitumor response following localized tumor irradiation presumably attributed to reactivation of antitumor immunity.

scholarly journals 905 FASN prevents immunogenicity of irradiated glioblastoma by inhibiting ER stress

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A950-A950
Author(s):  
Mara De Martino ◽  
Camille Daviaud ◽  
Claire Vanpouille-Box
Keyword(s):  
Er Stress ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Immune Escape ◽  
De Novo ◽  
Lipid Synthesis ◽  
Adult Brain ◽  
Immune Recognition

BackgroundGlioblastoma (GBM) is the most aggressive and incurable adult brain tumor. Radiation therapy (RT) is an essential modality for GBM treatment and is recognized to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD) subsequent to endoplasmic reticulum (ER) stress. However, RT also exacerbates potent immunosuppressive mechanisms that facilitate immune evasion. Notably, increased de novo lipid synthesis by the fatty acid synthase (FASN) is emerging as a mechanism of therapy resistance and immune escape. Here, we hypothesize that RT induces FASN to promote GBM survival and evade immune recognition by inhibiting ER stress and ICD.MethodsTo determine if lipid synthesis is altered in response to RT, we first assessed FASN expression by western blot (WB) and lipid accumulation by BODIPY staining in murine (CT2A and GL261) and human (U118) GBM cell lines. Next, FASN expression was blocked in CT2A cells using CRISPR-Cas9 or an inducible shRNA directed against Fasn to evaluate ICD and ER stress markers by ELISA, WB, and electron microscopy. Finally, CT2AshFASN cells or its non-silencing control (CT2AshNS) were orthotopically implanted and FASN knockdown was induced by feeding the mice with doxycycline. The immune contexture was determined by in situ immunofluorescence (n=3/group). Remaining mice were followed for survival (n=7/group).ResultsWe found that in vitro irradiation of GBM cells induces lipid accumulation in a dose-dependent fashion; an effect that is magnified over time lasting at least 6/7 days. Consistent with these findings, FASN expression was upregulated in irradiated GBM cells. Confirming the role of FASN, RT-induced accumulation of lipids was reverted when GBM cells were incubated with a FASN inhibitor. Next, we found that FASN ablation in CT2A cells induces mitochondria disruption and was sufficient to increase the expression of the ER stress makers BIP and CHOP. Along similar lines, shFASN enhances the secretion of the ICD markers HMGB1, IFN-beta and CXCL10 in irradiated CT2A cells. In vivo, CT2AshFASN tumors presented increased infiltration of CD11c+ cells and CD8+ T cells, consistent with prolonged mice survival (56 days vs. 28 days for CT2AshNS). Importantly, 43% of CT2AshFASN-bearing mice remained tumor-free for more than 70 days, while none of the CT2AshNS-bearing mice survived.ConclusionsAltogether, our data suggest that FASN-mediated lipid synthesis is an important mechanism to prevent ER stress, ICD, and anti-tumor immune responses in GBM. While much work remains to be done, our data propose FASN as a novel therapeutic target to overcome immunosuppression and sensitize GBM to immunotherapies.

scholarly journals Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

2020 ◽  
Author(s):  
Jie Mei ◽  
Yun Cai ◽  
Rui Xu ◽  
Xuejing Yang ◽  
Weijian Zhou ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Survival Data ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Methylation Status ◽  
Low Grade Glioma ◽  
Immune Checkpoints ◽  
Low Grade ◽  
Programmed Death

AbstractBackgroundImmune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet.MethodsA total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation in LGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.ResultsPD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes.ConclusionsHigh expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

scholarly journals Polyomavirus T Antigen InducesAPOBEC3BExpression Using an LXCXE-Dependent and TP53-Independent Mechanism

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Gabriel J. Starrett ◽  
Artur A. Serebrenik ◽  
Pieter A. Roelofs ◽  
Jennifer L. McCann ◽  
Brandy Verhalen ◽  
...  
Keyword(s):  
Immune Escape ◽  
Cytosine Deaminase ◽  
T Antigen ◽  
Tumor Evolution ◽  
Binding Motif ◽  
Cellular Mechanisms ◽  
Multiple Cancer ◽  
Additional Function ◽  
Acquired Drug Resistance ◽  
Wide Range

ABSTRACTAPOBEC3B is a single-stranded DNA cytosine deaminase with beneficial innate antiviral functions. However, misregulated APOBEC3B can also be detrimental by inflicting APOBEC signature C-to-T and C-to-G mutations in genomic DNA of multiple cancer types. Polyomavirus and papillomavirus oncoproteins induce APOBEC3B overexpression, perhaps to their own benefit, but little is known about the cellular mechanisms hijacked by these viruses to do so. Here we investigate the molecular mechanism of APOBEC3B upregulation by the polyomavirus large T antigen. First, we demonstrate that the upregulated APOBEC3B enzyme is strongly nuclear and partially localized to virus replication centers. Second, truncated T antigen (truncT) is sufficient for APOBEC3B upregulation, and the RB-interacting motif (LXCXE), but not the p53-binding domain, is required. Third, genetic knockdown of RB1 alone or in combination with RBL1 and/or RBL2 is insufficient to suppress truncT-mediated induction ofAPOBEC3B. Fourth, CDK4/6 inhibition by palbociclib is also insufficient to suppress truncT-mediated induction ofAPOBEC3B. Last, global gene expression analyses in a wide range of human cancers show significant associations between expression ofAPOBEC3Band other genes known to be regulated by the RB/E2F axis. These experiments combine to implicate the RB/E2F axis in promotingAPOBEC3Btranscription, yet they also suggest that the polyomavirus RB-binding motif has at least one additional function in addition to RB inactivation for triggeringAPOBEC3Bupregulation in virus-infected cells.IMPORTANCEThe APOBEC3B DNA cytosine deaminase is overexpressed in many different cancers and correlates with elevated frequencies of C-to-T and C-to-G mutations in 5′-TC motifs, oncogene activation, acquired drug resistance, and poor clinical outcomes. The mechanisms responsible for APOBEC3B overexpression are not fully understood. Here, we show that the polyomavirus truncated T antigen (truncT) triggers APOBEC3B overexpression through its RB-interacting motif, LXCXE, which in turn likely modulates the binding of E2F family transcription factors to promoteAPOBEC3Bexpression. This work strengthens the mechanistic linkage between active cell cycling, APOBEC3B overexpression, and cancer mutagenesis. Although this mutational mechanism damages cellular genomes, viruses may leverage it to promote evolution, immune escape, and pathogenesis. The cellular portion of the mechanism may also be relevant to nonviral cancers, where genetic mechanisms often activate the RB/E2F axis and APOBEC3B mutagenesis contributes to tumor evolution.

scholarly journals Checkpoint Inhibitors and Their Application in Breast Cancer

Breast Care ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Davide Bedognetti ◽  
Cristina Maccalli ◽  
Salha B.J. Al Bader ◽  
Francesco M. Marincola ◽  
Barbara Seliger
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Immune Surveillance ◽  
Significant Proportion ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Breast Cancers ◽  
Inhibitory Molecules

Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

scholarly journals Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation

2019 ◽  
Vol 59 (1) ◽  
pp. 237-261 ◽  
Author(s):  
Miguel Moutinho ◽  
Juan F. Codocedo ◽  
Shweta S. Puntambekar ◽  
Gary E. Landreth
Keyword(s):  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Nuclear Receptors ◽  
Motor Impairment ◽  
Therapeutic Approaches ◽  
New Findings ◽  
Wide Range ◽  
Preclinical And Clinical Studies ◽  
Lost In Translation

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.

scholarly journals Immunoistochemical expression of PD-1 and PD-L1 in bone marrow biopsies of patients with acute myeloid leukemia

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Romano ◽  
Antonino Giulio Giannone ◽  
Sergio Siragusa ◽  
Rossana Porcasi ◽  
Ada Maria Florena
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Medical Community ◽  
Immune Checkpoints ◽  
Bone Marrow Biopsies ◽  
Underlying Mechanisms ◽  
Acute Myeloid

tumor immunotherapy is a rapidly evolving field. The discovery of the ability of neoplasms to evade the immune response has shifted the attention of the medical community to the underlying mechanisms of the immune response to tumors, highlighting the importance of so-called immune check points, including CTLA4, TIM-3 and PD-1.  an immune escape mechanism is the activation of the immune checkpoint pathway that contributes to the creation of an immunosuppressive microenvironment and therefore to tumor proliferation.although immune checkpoints have been extensively investigated in solid tumors, the same is not true for hematologic neoplasms, particularly for myeloid malignancies. our study is based on the evaluation of the activation of the PD-1 and PD-L1 pathway in the context of the bone marrow tumor microenvironment of patients with acute myeloid leukemia. To do so we evaluated  34 bone marrow biopsies of patients with acute myeloid leukemia comparing them to 10 controls using immunohistochemical methods.

scholarly journals Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Thitinee Vanichapol ◽  
Somchai Chutipongtanate ◽  
Usanarat Anurathapan ◽  
Suradej Hongeng
Keyword(s):  
Immune System ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Escape ◽  
Adoptive Cell Therapy ◽  
Immune Recognition ◽  
T Cell Therapy ◽  
Cell Therapies

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma.

scholarly journals Europe and the Muslims: Debating the Foundations of State Policy

2021 ◽  
Vol 39 (1) ◽  
pp. 146-174
Author(s):  
Irina Starodubrovskaya ◽  
Keyword(s):  
State Policy ◽  
Political Islam ◽  
Theoretical Approaches ◽  
Wide Range ◽  
The Future ◽  
Main Driver ◽  
Western Values ◽  
Current Shift ◽  
Theoretical Issues ◽  
Western Democracies

This article discusses theoretical issues behind the current shift in the policy of European states towards Islamic communities. The shift is driven by the idea that the values of political Islam are incompatible with Western values; that the main driver behind radicalization is ideology and that even non‑violent Islamists gradually prepare the Muslim youth to embracing violence. Based on current academic discussions as well as the results of the author’s own research, the author concludes that the opponents of these ideas have serious counter‑ arguments. In their views, radicalization can be explained by a wide range of different factors. Violent and non‑violent Islamists compete for the audience, and therefore, not only can non‑violent Islamists embrace jihadist views but also, vice versa, some jihadists can change their position to non‑violence. Moreover, Muslim values, as well as those of the Islamists, are not necessarily antagonistic in all their aspects with the values of Western democracies. Various theoretical approaches form the basis for an alternative program of practical measures that could be implemented in the future.

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