The complex role of EZH2 in the tumor microenvironment: opportunities and challenges for immunotherapy combinations

2020 ◽  
Vol 12 (15) ◽  
pp. 1415-1430
Author(s):  
Jing Qiu ◽  
Shikhar Sharma ◽  
Robert A Rollins ◽  
Thomas A Paul
Keyword(s):  
Tumor Microenvironment ◽  
Cell Fate ◽  
Cell Function ◽  
Immune Dysfunction ◽  
Lymphoid Cells ◽  
Epigenetic Changes ◽  
Immune Effector ◽  
Effector Functions ◽  
Tumor Immunogenicity

Immune dysfunction in the tumor microenvironment occurs through epigenetic changes in both tumor cells and immune cells that alter transcriptional programs driving cell fate and cell function. Oncogenic activation of the histone methyltransferase EZH2 mediates gene expression changes, governing tumor immunogenicity as well as differentiation, survival and activation states of immune lineages. Emerging preclinical studies have highlighted the potential for EZH2 inhibitors to reverse epigenetic immune suppression in tumors and combine with immune checkpoint therapies. However, EZH2 activity is essential for the development of lymphoid cells, performing critical immune effector functions within tumors. In this review, we highlight the complexity of EZH2 function in immune regulation which may impact the implementation of combination with immunotherapy agents in clinic.

scholarly journals The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3542
Author(s):  
Joanna Domagala ◽  
Mieszko Lachota ◽  
Marta Klopotowska ◽  
Agnieszka Graczyk-Jarzynka ◽  
Antoni Domagala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

scholarly journals Dysregulation of the Leukocyte Signaling Landscape during Acute COVID-19

2021 ◽  
Author(s):  
Isaiah Turnbull ◽  
Anja Fuchs ◽  
Kenneth Remy ◽  
Michael Kelly ◽  
Elfaridah Frazier ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Tissue Injury ◽  
Ex Vivo ◽  
Myeloid Cell ◽  
Immune Dysfunction ◽  
Cellular Activation ◽  
Immune Effector ◽  
Systems Immunology ◽  
Stat3 Phosphorylation

Abstract The global COVID-19 pandemic has claimed the lives of more than 450,000 US citizens. Dysregulation of the immune system underlies the pathogenesis of COVID-19, with inflammation mediated local tissue injury to the lung in the setting of suppressed systemic immune function. To define the molecular mechanisms of immune dysfunction in COVID-19 we utilized a systems immunology approach centered on the circulating leukocyte phosphoproteome measured by mass cytometry. COVID-19 is associated with wholesale activation of a broad set of signaling pathways across myeloid and lymphoid cell populations. STAT3 phosphorylation predominated in both monocytes and T cells and was tightly correlated with circulating IL-6 levels. High levels of STAT3 phosphorylation was associated with decreased markers of myeloid cell maturation/activation and decreased ex-vivo T cell IFN-gamma production, demonstrating that during COVID-19 dysregulated cellular activation is associated with suppression of immune effector cell function. Collectively, these data reconcile the systemic inflammatory response and functional immunosuppression induced by COVID-19 and suggest STAT3 signaling may be the central pathophysiologic mechanism driving immune dysfunction in COVID-19.

scholarly journals The Emerging Role of Exosomes in Diagnosis, Prognosis, and Therapy in Head and Neck Cancer

2020 ◽  
Vol 21 (11) ◽  
pp. 4072 ◽  
Author(s):  
Linda Hofmann ◽  
Sonja Ludwig ◽  
Julius M. Vahl ◽  
Cornelia Brunner ◽  
Thomas K. Hoffmann ◽  
...  
Keyword(s):  
Cell Culture ◽  
Communication Network ◽  
Tumor Microenvironment ◽  
Head And Neck ◽  
Immune Suppression ◽  
Functional Role ◽  
Immune Dysfunction ◽  
Squamous Cell Carcinomas ◽  
Hnscc Cell

Exosomes, the smallest group of extracellular vesicles, carry proteins, miRNA, mRNA, DNA, and lipids, which they efficiently deliver to recipient cells, generating a communication network. Exosomes strongly contribute to the immune suppressive tumor microenvironment of head and neck squamous cell carcinomas (HNSCC). Isolation of exosomes from HNSCC cell culture or patient’s plasma allows for analyzing their molecular cargo and functional role in immune suppression and tumor progression. Immune affinity-based separation of different exosome subsets, such as tumor-derived or T cell-derived exosomes, from patient’s plasma simultaneously informs about tumor status and immune dysfunction. In this review, we discuss the recent understanding of how exosomes behave in the HNSCC tumor microenvironment and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy in HNSCC.

Abstract 641: The Role of Interleukin-23 in the Development of Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Aliia Fatkhullina ◽  
Iuliia Peshkova ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Chronic Inflammatory Disease ◽  
Lymphoid Cells ◽  
Efficient Manner ◽  
Mediators Of Inflammation

Atherosclerosis is lipid-driven chronic inflammatory disease of the arterial wall mediated by innate and adaptive immune responses. Inflammation promotes the development atherosclerotic plaques. Cytokines are soluble mediators of inflammation and important players in the pathogenesis of atherosclerosis. IL-23, a cytokine of IL-6/IL-12 cytokines superfamily is produced by myeloid cells and regulates the production of IL-17 and IL-22 by T helper IL-17 producing (Th17) cells, innate lymphoid cells of type 3 (ILC3) and gamma delta T cells in various auto-inflammatory diseases. IL-23R expression was also detected on myeloid cells but its role in regulation of myeloid cell function is not well defined. The level of IL-23 was shown to be upregulated in cardiovascular pathologies. Therefore, we decided to address the role of IL-23 in atherosclerosis using Il23p19 and Il23(R) receptor deficient mice. Surprisingly, atherosclerosis prone, Ldlr -/- mice transplanted with Il23p19 -/- or Il23r -/- bone marrow and fed with Western diet (WD) for 14 weeks demonstrated acceleration of atherosclerosis progression, which was characterized by increased accumulation of various hematopoietic cells in the aortas. Analysis of cytokine production unexpectedly revealed no changes in IL-17A and IFN-gamma production among CD4 T cells in the aortas. This effect was specific to aortas, as IL-17A production in the intestine of Il23p19 -/- mice was reduced, similarly to previously published observations. On the other hand, macrophages from Il23p19 -/- mice were able to uptake oxLDL in more efficient manner compared to wt controls, suggesting the regulatory role of IL-23 in foam cells formation. We also found enhanced inflammatory gene expression in aortas of Il23p19 -/- -> Ldlr -/- and Il23r -/- -> Ldlr -/- mice compared to wt controls. Overall our data suggest IL-17 independent atheroprotective role of IL-23.

scholarly journals The Role of TOX in the Development of Innate Lymphoid Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Corey R. Seehus ◽  
Jonathan Kaye
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
Natural Killer ◽  
Cell Fate ◽  
Lymphoid Cell ◽  
Adaptive Immune System ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Innate Lymphoid Cell

TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

scholarly journals 568 Tumor-derived GDF-15 prevents therapy success of checkpoint inhibitors by blocking T-lymphocyte recruitment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A597-A597
Author(s):  
Markus Haake ◽  
Tina Schäfer ◽  
Beatrice Haack ◽  
Neha Vashist ◽  
Sabrina Genßler ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Serum Levels ◽  
Lymphoid Cells ◽  
Cell Infiltration ◽  
Baseline Serum ◽  
Immune Effector ◽  
Local Immunosuppression ◽  
Melanoma Patients ◽  
The Impact

BackgroundImmune checkpoint blockade (ICB) can achieve durable responses in a subgroup of patients with metastatic cancer, only. Poor immune effector cell infiltration into the tumor microenvironment is a major obstacle to successful therapy. Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily and has been linked to feto-maternal tolerance, anorexia but recently also to potent local immunosuppression under physiologic and pathophysiologic conditions. GDF-15 is overexpressed in a wide variety of tumors and may be key factor produced by tumors to prevent effective immune cell infiltration into the tumor and to potently block checkpoint inhibitor activity.MethodsEffects of recombinant GDF-15 and a proprietary GDF-15 neutralizing antibody (CTL-002) on immune cell trafficking and activation were analyzed by adhesion and interaction assays and in melanoma-bearing humanized mouse models. The impact of GDF-15 overexpression was tested in subcutaneously implanted, GDF-15-transgenic MC38 cells. Additionally, patient GDF-15 serum levels were correlated with immune infiltration and OS in cutaneous melanoma. Associations between GDF-15 serum levels, response to PD-1-based ICB and corresponding OS were assessed in two independent cohorts of melanoma patients.ResultsGDF-15 impairs adhesion of T and NK cells on activated endothelia. In HV18-MK bearing humanized mice, inhibition of GDF-15 strongly enhances infiltration of activated myeloid and lymphoid cells. In MC38 tumors, GDF-15 overexpression can abrogate tumor rejection upon anti-PD-1 therapy. 50% of the mice with GDF-15 overexpressing tumors were, however, rescued when anti-PD-1 was combined with anti-GDF-15 (CTL-002). Likewise, anti-GDF-15 improved responses to anti-CD40 + poly(I:C) in the same tumor model. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for melanoma brain metastases. In two independent melanoma patient cohorts, low baseline serum GDF-15 levels predicted clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 is an independently predictor for poor survival in anti-PD-1 treated melanoma patients.ConclusionsTumor-derived GDF-15 blocks the infiltration of immune effector cells into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of immune cells to extravasate blood vessels and enter the tumor microenvironment in vivo. GDF-15 thus represents a promising target for cancer immunotherapy. Antibodies against GDF-15 may support treatments with anti-PD-1 and other immunotherapeutic agents. A clinical trial combining anti-GDF-15 (CTL002) with anti-PD-1 (NCT04725474, submitted Abstract ID 15073) is ongoing.Ethics ApprovalUse of patient samples for this study had been approved by the institutional ethics committee Tübingen (ethic vote 125/2015BO2). Use of surplus sera collected in the University of Zurich Hospital (USZ) Biobank during routine blood draws from consenting metastatic melanoma patients was performed according to IRB approval (KEK.Zh- 647/800) and followed the Declaration of Helsinki on Human Rights.ConsentAll patients had given written informed consent to have clinical data recorded by the Central Malignant Melanoma Registry (CMMR) database.

scholarly journals Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy

2014 ◽  
Vol 8 (1) ◽  
pp. 66-78 ◽  
Author(s):  
Vikram Mehraj ◽  
Mohammad-Ali Jenabian ◽  
Kishanda Vyboh ◽  
Jean-Pierre Routy
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Cell Function ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Immune Dysfunction ◽  
Hiv Pathogenesis ◽  
Host Restriction

Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication.

scholarly journals The IL-10GFP (VeRT-X) mouse strain is not suitable for the detection of IL-10 production by granulocytes during lung inflammation

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0247895
Author(s):  
Müge Özkan ◽  
Yusuf Cem Eskiocak ◽  
Gerhard Wingender
Keyword(s):  
Immune Responses ◽  
Lung Diseases ◽  
Myeloid Cells ◽  
Lymphoid Cells ◽  
Reporter Strain ◽  
Immune Effector ◽  
Effector Functions ◽  
Gfp Reporter ◽  
Unequivocal Identification ◽  
Clear Identification

The clear and unequivocal identification of immune effector functions is essential to understand immune responses. The cytokine IL-10 is a critical immune regulator and was shown, for example, to limit pathology during various lung diseases. However, the clear identification of IL-10-producing cells is challenging and, therefore, reporter mouse lines were developed to facilitate their detection. Several such reporter lines utilize GFP, including the IL-10GFP (VeRT-X) reporter strain studied here. In line with previous reports, we found that this IL-10GFP line faithfully reports on the IL-10 production of lymphoid cells. However, we show that the IL-10GFP reporter is not suitable to analyse IL-10 production of myeloid cells during inflammation. During inflammation, the autofluorescence of myeloid cells increased to an extent that entirely masked the IL-10-specific GFP-signal. Our data illustrate a general and important technical caveat using GFP-reporter lines for the analysis of myeloid cells and suggest that previous reports on effector functions of myeloid cells using such GFP-based reporters might require re-evaluation.

scholarly journals PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia

Blood ◽  
2015 ◽  
Vol 126 (2) ◽  
pp. 203-211 ◽  
Author(s):  
Fabienne McClanahan ◽  
Bola Hanna ◽  
Shaun Miller ◽  
Andrew James Clear ◽  
Peter Lichter ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Immune Dysfunction ◽  
Lymphocytic Leukemia ◽  
Cell Populations ◽  
Transfer Model ◽  
Immune Effector ◽  
Effector Functions ◽  
Key Points ◽  
Leukemia Development

Key Points In vivo PD-L1 blockade prevents CLL development in the Eµ-TCL1 adoptive transfer model. In vivo PD-L1 blockade normalizes T-cell and myeloid cell populations and immune effector functions.

scholarly journals Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2969 ◽  
Author(s):  
Marc Hilmi ◽  
Rémy Nicolle ◽  
Corinne Bousquet ◽  
Cindy Neuzillet
Keyword(s):  
Tumor Microenvironment ◽  
Immune Evasion ◽  
Lymphoid Cells ◽  
Cancer Associated Fibroblasts ◽  
Tumor Immune Evasion ◽  
Promising Strategy ◽  
Extracellular Matrix Components ◽  
Potential Applications ◽  
Matrix Components

Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.

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