scholarly journals PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy

2020 ◽  
Vol 21 (15) ◽  
pp. 5337 ◽  
Author(s):  
Fabiana Conciatori ◽  
Chiara Bazzichetto ◽  
Italia Falcone ◽  
Ludovica Ciuffreda ◽  
Gianluigi Ferretti ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Predictive Biomarkers ◽  
Point Of View ◽  
Solid Cancer ◽  
Host Immune System ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
And Function ◽  
Promising Development

Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic strategies, many of these still fail from a clinical point of view, probably due to the lack of prognostic and predictive biomarkers. In that respect, several data shed new light on the role of the tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) in affecting the composition and function of the tumor microenvironment (TME) as well as resistance/sensitivity to immunotherapy. In this review, we summarize current knowledge on PTEN functions in different TME compartments (immune and stromal cells) and how they can modulate sensitivity/resistance to different immunological manipulations and ultimately influence clinical response to cancer immunotherapy.

scholarly journals Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1525 ◽  
Author(s):  
Geny Piro ◽  
Carmine Carbone ◽  
Luisa Carbognin ◽  
Sara Pilotto ◽  
Chiara Ciccarese ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cancer Immunoediting ◽  
Multiple Tumor ◽  
Cellular Processes ◽  
Tensin Homolog ◽  
Future Clinical Practice ◽  
Cancer Intervention

Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the usefulness of immunotherapy due to the activation of several escape mechanisms. Indeed, the tumor microenvironment has an almost full immunosuppressive profile, creating an obstacle to therapeutic treatment. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) governs a plethora of cellular processes, including maintenance of genomic stability, cell survival/apoptosis, migration, and metabolism. The repertoire of PTEN functions has recently been expanded to include regulation of the tumor microenvironment and immune system, leading to a drastic reevaluation of the canonical paradigm of PTEN action with new potential implications for immunotherapy-based approaches. Understanding the implication of PTEN in cancer immunoediting and immune evasion is crucial to develop new cancer intervention strategies. Recent evidence has shown a double context-dependent role of PTEN in anticancer immunity. Here we summarize the current knowledge of PTEN’s role at a crossroads between tumor and immune compartments, highlighting the most recent findings that are likely to change future clinical practice.

scholarly journals Immunohistochemical Characterization of Phosphorylated Ubiquitin in the Mouse Hippocampus

2020 ◽  
Author(s):  
Kosuke Kataoka ◽  
Andras Bilkei-Gorzo ◽  
Andreas Zimmer ◽  
Toru Asahi
Keyword(s):  
Cell Layer ◽  
Granule Cell Layer ◽  
Phosphatase And Tensin Homolog ◽  
Neuronal Markers ◽  
Tensin Homolog ◽  
Evolutionarily Conserved ◽  
Previous Hypothesis ◽  
Mouse Hippocampus ◽  
And Function

ABSTRACTMitochondrial autophagy (mitophagy) is an essential and evolutionarily conserved process that maintains mitochondrial integrity via the removal of damaged or superfluous mitochondria in eukaryotic cells. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin promote mitophagy and function in a common signaling pathway. PINK1-mediated ubiquitin phosphorylation at Serine 65 (Ser65-pUb) is a key event in the efficient execution of PINK1/Parkin-dependent mitophagy. However, few studies have used immunohistochemistry to analyze Ser65-pUb in the mouse. Here, we examined the immunohistochemical characteristics of Ser65-pUb in the mouse hippocampus. Some hippocampal cells were Ser65-pUb positive, whereas the remaining cells expressed no or low levels of Ser65-pUb. PINK1 deficiency resulted in a decrease in the density of Ser65-pUb-positive cells, consistent with a previous hypothesis based on in vitro research. Interestingly, Ser65-pUb-positive cells were detected in hippocampi lacking PINK1 expression. The CA3 pyramidal cell layer and the dentate gyrus (DG) granule cell layer exhibited significant reductions in the density of Ser65-pUb-positive cells in PINK1-deficient mice. Moreover, Ser65-pUb immunoreactivity colocalized predominantly with neuronal markers. These findings suggest that Ser65-pUb may serve as a biomarker of in situ PINK1 signaling in the mouse hippocampus; however, the results should be interpreted with caution, as PINK1 deficiency downregulated Ser65-pUb only partially.

scholarly journals PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

2020 ◽  
Vol 21 (5) ◽  
pp. 1772 ◽  
Author(s):  
Lucia Barazzuol ◽  
Flavia Giamogante ◽  
Marisa Brini ◽  
Tito Calì
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Selective Degradation ◽  
Contact Sites ◽  
Tensin Homolog

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

scholarly journals Mutual Interplay of Host Immune System and Gut Microbiota in the Immunopathology of Atherosclerosis

2020 ◽  
Vol 21 (22) ◽  
pp. 8729 ◽  
Author(s):  
Chih-Fan Yeh ◽  
Ying-Hsien Chen ◽  
Sheng-Fu Liu ◽  
Hsien-Li Kao ◽  
Ming-Shiang Wu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cytokine Production ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Host Immune System ◽  
Gut Permeability ◽  
And Function ◽  
Progression Of Atherosclerosis

Inflammation is the key for the initiation and progression of atherosclerosis. Accumulating evidence has revealed that an altered gut microbiome (dysbiosis) triggers both local and systemic inflammation to cause chronic inflammatory diseases, including atherosclerosis. There have been some microbiome-relevant pro-inflammatory mechanisms proposed to link the relationships between dysbiosis and atherosclerosis such as gut permeability disruption, trigger of innate immunity from lipopolysaccharide (LPS), and generation of proatherogenic metabolites, such as trimethylamine N-oxide (TMAO). Meanwhile, immune responses, such as inflammasome activation and cytokine production, could reshape both composition and function of the microbiota. In fact, the immune system delicately modulates the interplay between microbiota and atherogenesis. Recent clinical trials have suggested the potential of immunomodulation as a treatment strategy of atherosclerosis. Here in this review, we present current knowledge regarding to the roles of microbiota in contributing atherosclerotic pathogenesis and highlight translational perspectives by discussing the mutual interplay between microbiota and immune system on atherogenesis.

scholarly journals PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior

2019 ◽  
Author(s):  
Cristina Sánchez-Puelles ◽  
María Calleja-Felipe ◽  
Alberto Ouro ◽  
Ghassen Bougamra ◽  
Ana Arroyo ◽  
...  
Keyword(s):  
Social Interactions ◽  
Synaptic Depression ◽  
Synaptic Proteins ◽  
Pten Gene ◽  
Neuronal Structure ◽  
Phosphatase And Tensin Homolog ◽  
Behavioral Traits ◽  
Genetic Manipulations ◽  
Tensin Homolog ◽  
And Function

Abstract Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior.

scholarly journals Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1162
Author(s):  
Bohai Feng ◽  
Jochen Hess
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Current Knowledge ◽  
Immune Surveillance ◽  
Predictive Biomarkers ◽  
Small Subset ◽  
Host Immune System ◽  
Omics Data ◽  
Holistic View

Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains low and only a small subset of head and neck cancer patients achieves a durable clinical benefit. The availability of multi-omics data and emerging computational technologies facilitate not only a deeper understanding of the cellular composition in the tumor immune microenvironment but also enables the study of molecular principles in the complex regulation of immune surveillance versus tolerance. These knowledges will pave the way to apply immunotherapy more precisely and effectively. This review aims to provide a holistic view on how the immune landscape dictates the tumor fate and vice versa, and how integrative analysis of multi-omics data contribute to our current knowledge on the accuracy of predictive biomarkers and on a broad range of factors influencing the response to immunotherapy in head and neck cancer.

scholarly journals Siglec Signaling in the Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Eline J. H. van Houtum ◽  
Christian Büll ◽  
Lenneke A. M. Cornelissen ◽  
Gosse J. Adema
Keyword(s):  
Sialic Acid ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Current Knowledge ◽  
Surface Distribution ◽  
Tumor Immune Evasion ◽  
Binding Preference ◽  
Ligand Expression ◽  
And Function ◽  
Tumor Types

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors that recognize sialoglycans – sialic acid containing glycans that are abundantly present on cell membranes. Siglecs are expressed on most immune cells and can modulate their activity and function. The majority of Siglecs contains immune inhibitory motifs comparable to the immune checkpoint receptor PD-1. In the tumor microenvironment (TME), signaling through the Siglec-sialoglycan axis appears to be enhanced through multiple mechanisms favoring tumor immune evasion similar to the PD-1/PD-L1 signaling pathway. Siglec expression on tumor-infiltrating immune cells appears increased in the immune suppressive microenvironment. At the same time, enhanced Siglec ligand expression has been reported for several tumor types as a result of aberrant glycosylation, glycan modifications, and the increased expression of sialoglycans on proteins and lipids. Siglec signaling has been identified as important regulator of anti-tumor immunity in the TME, but the key factors contributing to Siglec activation by tumor-associated sialoglycans are diverse and poorly defined. Among others, Siglec activation and signaling are co-determined by their expression levels, cell surface distribution, and their binding preferences for cis- and trans-ligands in the TME. Siglec binding preference are co-determined by the nature of the proteins/lipids to which the sialoglycans are attached and the multivalency of the interaction. Here, we review the current understanding and emerging conditions and factors involved in Siglec signaling in the TME and identify current knowledge gaps that exist in the field.

scholarly journals Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity

2021 ◽  
Vol 22 (22) ◽  
pp. 12429
Author(s):  
Carl Randall Harrell ◽  
Ana Volarevic ◽  
Valentin G. Djonov ◽  
Nemanja Jovicic ◽  
Vladislav Volarevic
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Cellular Mechanisms ◽  
Multipotent Stem Cells ◽  
And Function

Mesenchymal stem cells (MSCs) are self-renewable, multipotent stem cells that regulate the phenotype and function of all immune cells that participate in anti-tumor immunity. MSCs modulate the antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells and regulate the generation and expansion of myeloid-derived suppressor cells and T regulatory cells. As plastic cells, MSCs adopt their phenotype and function according to the cytokine profile of neighboring tumor-infiltrated immune cells. Depending on the tumor microenvironment to which they are exposed, MSCs may obtain pro- and anti-tumorigenic phenotypes and may enhance or suppress tumor growth. Due to their tumor-homing properties, MSCs and their exosomes may be used as vehicles for delivering anti-tumorigenic agents in tumor cells, attenuating their viability and invasive characteristics. Since many factors affect the phenotype and function of MSCs in the tumor microenvironment, a better understanding of signaling pathways that regulate the cross-talk between MSCs, immune cells and tumor cells will pave the way for the clinical use of MSCs in cancer immunotherapy. In this review article, we summarize current knowledge on the molecular and cellular mechanisms that are responsible for the MSC-dependent modulation of the anti-tumor immune response and we discuss different insights regarding therapeutic potential of MSCs in the therapy of malignant diseases.

scholarly journals Metastasis-associated Protein 1/Histone Deacetylase 4-Nucleosome Remodeling and Deacetylase Complex Regulates Phosphatase and Tensin Homolog Gene Expression and Function

2012 ◽  
Vol 287 (33) ◽  
pp. 27843-27850 ◽  
Author(s):  
Sirigiri Divijendra Natha Reddy ◽  
Suresh B. Pakala ◽  
Poonam R. Molli ◽  
Neil Sahni ◽  
Narasimha Kumar Karanam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Nucleosome Remodeling ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Histone Deacetylase 4 ◽  
And Function

scholarly journals The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment

2015 ◽  
Vol 1 (10) ◽  
pp. e1500845 ◽  
Author(s):  
Madhav D. Sharma ◽  
Rahul Shinde ◽  
Tracy L. McGaha ◽  
Lei Huang ◽  
Rikke B. Holmgaard ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phosphatase And Tensin Homolog ◽  
Effector Cells ◽  
Multiple Tumor ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Immunosuppressive Tumor Microenvironment ◽  
Specialized Form ◽  
Tumor Types ◽  
Inflammatory Milieu

The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.

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