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Article: Enabling CAR-T cells for solid tumors: Rage against the suppressive tumor microenvironment.

Antoñana-Vildosola, Asier / Zanetti, Samanta Romina / Palazon, Asis

International review of cell and molecular biology

2022 Volume 370, Page(s) 123–147

Abstract: Adoptive T cell therapies based on chimeric antigen receptors (CAR-T) are emerging as genuine therapeutic options for the treatment of hematological malignancies. The observed clinical success has not yet been extended into solid tumor indications as a ... ...

Abstract	Adoptive T cell therapies based on chimeric antigen receptors (CAR-T) are emerging as genuine therapeutic options for the treatment of hematological malignancies. The observed clinical success has not yet been extended into solid tumor indications as a result of multiple factors including immunosuppressive features of the tumor microenvironment (TME). In this context, an emerging strategy is to design CAR-T cells for the elimination of defined cellular components of the TME, with the objective of re-shaping the tumor immune contexture to control tumor growth. Relevant cell components that are currently under investigation as targets of CAR-T therapies include the tumor vasculature, cancer-associated fibroblasts (CAFs), and immunosuppressive tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs). In this review, we recapitulate the rapidly expanding field of CAR-T cell therapies that directly target cellular components within the TME with the ultimate objective of promoting immune function, either alone or in combination with other cancer therapies.
MeSH term(s)	Humans ; Immunotherapy, Adoptive ; Neoplasms/pathology ; Receptors, Chimeric Antigen ; T-Lymphocytes ; Tumor Microenvironment
Chemical Substances	Receptors, Chimeric Antigen
Language	English
Publishing date	2022-05-23
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2427220-6
ISSN	1937-6448 ; 0074-7696
ISSN	1937-6448 ; 0074-7696
DOI	10.1016/bs.ircmb.2022.03.004
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Article ; Online: CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape.

Rodriguez-Garcia, Alba / Palazon, Asis / Noguera-Ortega, Estela / Powell, Daniel J / Guedan, Sonia

Frontiers in immunology

2020 Volume 11, Page(s) 1109

Abstract: Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy for the treatment of hematological malignancies. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. A ... ...

Abstract	Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy for the treatment of hematological malignancies. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. A major obstacle for CAR-T cells is the intrinsic ability of tumors to evade immune responses. Advanced solid tumors are largely composed of desmoplastic stroma and immunosuppressive modulators, and characterized by aberrant cell proliferation and vascularization, resulting in hypoxia and altered nutrient availability. To mount a curative response after infusion, CAR-T cells must infiltrate the tumor, recognize their cognate antigen and perform their effector function in this hostile tumor microenvironment, to then differentiate and persist as memory T cells that confer long-term protection. Fortunately, recent advances in synthetic biology provide a wide set of tools to genetically modify CAR-T cells to overcome some of these obstacles. In this review, we provide a comprehensive overview of the key tumor intrinsic mechanisms that prevent an effective CAR-T cell antitumor response and we discuss the most promising strategies to prevent tumor escape to CAR-T cell therapy.
MeSH term(s)	Animals ; Extracellular Matrix/immunology ; Fibroblasts/immunology ; Humans ; Immune Checkpoint Proteins/immunology ; Immunotherapy, Adoptive ; Lymphocytes, Tumor-Infiltrating/immunology ; Macrophages/immunology ; Mice ; Models, Immunological ; Myeloid-Derived Suppressor Cells/immunology ; Neoplasms/blood supply ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Chimeric Antigen/immunology ; T-Lymphocytes, Regulatory/immunology ; Tumor Escape/immunology ; Tumor Hypoxia/immunology ; Tumor Microenvironment/immunology
Chemical Substances	Immune Checkpoint Proteins ; Receptors, Chimeric Antigen
Language	English
Publishing date	2020-06-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01109
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Article ; Online: The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.

Foskolou, Iosifina P / Cunha, Pedro P / Sánchez-López, Elena / Minogue, Eleanor A / Nicolet, Benoît P / Guislain, Aurélie / Jorgensen, Christian / Kostidis, Sarantos / Zandhuis, Nordin D / Barbieri, Laura / Bargiela, David / Nathanael, Demitris / Tyrakis, Petros A / Palazon, Asis / Giera, Martin / Wolkers, Monika C / Johnson, Randall S

Cell reports

2023 Volume 42, Issue 9, Page(s) 113013

Abstract: 2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two ...

Abstract	2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8
MeSH term(s)	Humans ; T-Lymphocytes, Cytotoxic/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Glutarates/metabolism ; Neoplasms/metabolism ; Isocitrate Dehydrogenase
Chemical Substances	alpha-hydroxyglutarate (2889-31-8) ; Glutarates ; Isocitrate Dehydrogenase (EC 1.1.1.41)
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113013
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Article ; Online: Factor-inhibiting HIF (FIH) promotes lung cancer progression.

García-Del Río, Ana / Prieto-Fernández, Endika / Egia-Mendikute, Leire / Antoñana-Vildosola, Asier / Jimenez-Lasheras, Borja / Lee, So Young / Barreira-Manrique, Adrián / Zanetti, Samanta Romina / de Blas, Ander / Velasco-Beltrán, Paloma / Bosch, Alexandre / Aransay, Ana M / Palazon, Asis

JCI insight

2023 Volume 8, Issue 20

Abstract: Factor-inhibiting HIF (FIH) is an asparagine hydroxylase that acts on hypoxia-inducible factors (HIFs) to control cellular adaptation to hypoxia. FIH is expressed in several tumor types, but its impact in tumor progression remains largely unexplored. We ... ...

Abstract	Factor-inhibiting HIF (FIH) is an asparagine hydroxylase that acts on hypoxia-inducible factors (HIFs) to control cellular adaptation to hypoxia. FIH is expressed in several tumor types, but its impact in tumor progression remains largely unexplored. We observed that FIH was expressed on human lung cancer tissue. Deletion of FIH in mouse and human lung cancer cells resulted in an increased glycolytic metabolism, consistent with increased HIF activity. FIH-deficient lung cancer cells exhibited decreased proliferation. Analysis of RNA-Seq data confirmed changes in the cell cycle and survival and revealed molecular pathways that were dysregulated in the absence of FIH, including the upregulation of angiomotin (Amot), a key component of the Hippo tumor suppressor pathway. We show that FIH-deficient tumors were characterized by higher immune infiltration of NK and T cells compared with FIH competent tumor cells. In vivo studies demonstrate that FIH deletion resulted in reduced tumor growth and metastatic capacity. Moreover, high FIH expression correlated with poor overall survival in non-small cell lung cancer (NSCLC). Our data unravel FIH as a therapeutic target for the treatment of lung cancer.
MeSH term(s)	Humans ; Animals ; Mice ; Lung Neoplasms/genetics ; Carcinoma, Non-Small-Cell Lung/genetics ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Repressor Proteins/metabolism ; Hypoxia
Chemical Substances	Mixed Function Oxygenases (EC 1.-) ; Repressor Proteins
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.167394
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Article: Assessing the Mobility of Severe Acute Respiratory Syndrome Coronavirus-2 Spike Protein Glycans by Structural and Computational Methods.

Stagnoli, Soledad / Peccati, Francesca / Connell, Sean R / Martinez-Castillo, Ane / Charro, Diego / Millet, Oscar / Bruzzone, Chiara / Palazon, Asis / Ardá, Ana / Jiménez-Barbero, Jesús / Ereño-Orbea, June / Abrescia, Nicola G A / Jiménez-Osés, Gonzalo

Frontiers in microbiology

2022 Volume 13, Page(s) 870938

Abstract: Two years after its emergence, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several vaccines. The extensively glycosylated ...

Abstract	Two years after its emergence, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several vaccines. The extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin converting enzyme 2 (ACE2) through its receptor binding domain (RBD), is the major target of neutralizing antibodies. Like to many other viral fusion proteins, the SARS-CoV-2 spike protein utilizes a glycan shield to thwart the host immune response. To grasp the influence of chemical signatures on carbohydrate mobility and reconcile the cryo-EM density of specific glycans we combined our cryo-EM map of the S ectodomain to 4.1 Å resolution, reconstructed from a limited number of particles, and all-atom molecular dynamics simulations. Chemical modifications modeled on representative glycans (defucosylation, sialylation and addition of terminal LacNAc units) show no significant influence on either protein shielding or glycan flexibility. By estimating at selected sites the local correlation between the full density map and atomic model-based maps derived from molecular dynamics simulations, we provide insight into the geometries of the α-Man-(1→3)-[α-Man-(1→6)-]-β-Man-(1→4)-β-GlcNAc(1→4)-β-GlcNAc core common to all
Language	English
Publishing date	2022-04-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2022.870938
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Article ; Online: Factor-inhibiting HIF (FIH) promotes lung cancer progression

Ana García-del Río / Endika Prieto-Fernández / Leire Egia-Mendikute / Asier Antoñana-Vildosola / Borja Jimenez-Lasheras / So Young Lee / Adrián Barreira-Manrique / Samanta Romina Zanetti / Ander de Blas / Paloma Velasco-Beltrán / Alexandre Bosch / Ana M. Aransay / Asis Palazon

JCI Insight, Vol 8, Iss

2023 Volume 20

Abstract	Factor-inhibiting HIF (FIH) is an asparagine hydroxylase that acts on hypoxia-inducible factors (HIFs) to control cellular adaptation to hypoxia. FIH is expressed in several tumor types, but its impact in tumor progression remains largely unexplored. We observed that FIH was expressed on human lung cancer tissue. Deletion of FIH in mouse and human lung cancer cells resulted in an increased glycolytic metabolism, consistent with increased HIF activity. FIH-deficient lung cancer cells exhibited decreased proliferation. Analysis of RNA-Seq data confirmed changes in the cell cycle and survival and revealed molecular pathways that were dysregulated in the absence of FIH, including the upregulation of angiomotin (Amot), a key component of the Hippo tumor suppressor pathway. We show that FIH-deficient tumors were characterized by higher immune infiltration of NK and T cells compared with FIH competent tumor cells. In vivo studies demonstrate that FIH deletion resulted in reduced tumor growth and metastatic capacity. Moreover, high FIH expression correlated with poor overall survival in non–small cell lung cancer (NSCLC). Our data unravel FIH as a therapeutic target for the treatment of lung cancer.
Keywords	Cell biology ; Medicine ; R
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immune response regulation in the tumor microenvironment by hypoxia.

Labiano, Sara / Palazon, Asis / Melero, Ignacio

Seminars in oncology

2015 Volume 42, Issue 3, Page(s) 378–386

Abstract: Lymphocytes and myeloid cells sense hypoxia by the hypoxia-inducible factor (HIF) transcriptional system and via other molecular mechanisms. Low O2 availability is a hallmark of most solid tumors in which infiltrating leukocytes experience severe hypoxia ...

Abstract	Lymphocytes and myeloid cells sense hypoxia by the hypoxia-inducible factor (HIF) transcriptional system and via other molecular mechanisms. Low O2 availability is a hallmark of most solid tumors in which infiltrating leukocytes experience severe hypoxia once away from nurturing blood vessels. HIF controls migration, differentiation, and effector functions on immune cells. Importantly, in the tumor microenvironment the hypoxia response modulates the expression levels for important molecular targets in immunotherapy such as CD137, OX-40, FOXP3, and PD-L1. Modulation by hypoxia of tumor-associated macrophages, myeloid-derived suppressor cells, and dendritic cells ought to play an important underexplored role in modulating tumor immunity. Overall, low O2 seems to invigorate some anti-tumor effector T-cell functions while conflictingly favoring T-regulatory cells (Tregs) in terms of their differentiation, suppressive functions, and recruitment. Hypoxia also has been shown to uphold myeloid cell-mediated tumor-promoting inflammation and the immunosuppressive functions of tumor-associated macrophages. Detailed research of this intricate and poorly understood balance is warranted to improve the outcome of cancer immunotherapy.
MeSH term(s)	Adaptive Immunity ; Animals ; Cell Hypoxia/immunology ; Dendritic Cells/immunology ; Humans ; Immunity, Innate ; Killer Cells, Natural/immunology ; Neoplasms/immunology ; Neoplasms/metabolism ; T-Lymphocytes/immunology ; Tumor Microenvironment/immunology
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	189220-4
ISSN	1532-8708 ; 0093-7754
ISSN (online)	1532-8708
ISSN	0093-7754
DOI	10.1053/j.seminoncol.2015.02.009
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Article ; Online: Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b.

Nature communications

2023 Volume 14, Issue 1, Page(s) 3496

Abstract: Sialic acid-binding Ig-like lectin 15 (Siglec-15) is an immune modulator and emerging cancer immunotherapy target. However, limited understanding of its structure and mechanism of action restrains the development of drug candidates that unleash its full ... ...

Abstract	Sialic acid-binding Ig-like lectin 15 (Siglec-15) is an immune modulator and emerging cancer immunotherapy target. However, limited understanding of its structure and mechanism of action restrains the development of drug candidates that unleash its full therapeutic potential. In this study, we elucidate the crystal structure of Siglec-15 and its binding epitope via co-crystallization with an anti-Siglec-15 blocking antibody. Using saturation transfer-difference nuclear magnetic resonance (STD-NMR) spectroscopy and molecular dynamics simulations, we reveal Siglec-15 binding mode to α(2,3)- and α(2,6)-linked sialic acids and the cancer-associated sialyl-Tn (STn) glycoform. We demonstrate that binding of Siglec-15 to T cells, which lack STn expression, depends on the presence of α(2,3)- and α(2,6)-linked sialoglycans. Furthermore, we identify the leukocyte integrin CD11b as a Siglec-15 binding partner on human T cells. Collectively, our findings provide an integrated understanding of the structural features of Siglec-15 and emphasize glycosylation as a crucial factor in controlling T cell responses.
MeSH term(s)	Humans ; Crystallization ; Epitopes ; Glycosylation ; Integrins ; T-Lymphocytes
Chemical Substances	Epitopes ; Integrins ; ITGAM protein, human ; SIGLEC15 protein, human
Language	English
Publishing date	2023-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39119-8
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Article: A cell-engineered system to assess tumor cell sensitivity to CD8

Nelson, Nadine / Lopez-Pelaez, Marta / Palazon, Asis / Poon, Edmund / De La Roche, Maike / Barry, Simon / Valge-Archer, Viia / Wilkinson, Robert W / Dovedi, Simon J / Smith, Paul D

Oncoimmunology

2019 Volume 8, Issue 8, Page(s) 1599635

Abstract: ... In ... ...

Abstract	In vitro
Language	English
Publishing date	2019-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2019.1599635
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Article ; Online: Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment.

Prieto-Fernández, Endika / Egia-Mendikute, Leire / Bosch, Alexandre / García Del Río, Ana / Jimenez-Lasheras, Borja / Antoñana-Vildosola, Asier / Lee, So Young / Palazon, Asis

Frontiers in immunology

2020 Volume 11, Page(s) 586977

Abstract: The syndecan (Sdc) family is comprised of four members of cell surface molecules (Sdc-1 to 4) with different biological functions. Syndecan-3 (Sdc-3) is known to be mainly expressed in the brain and nervous tissue and plays a key role in development, ... ...

Abstract	The syndecan (Sdc) family is comprised of four members of cell surface molecules (Sdc-1 to 4) with different biological functions. Syndecan-3 (Sdc-3) is known to be mainly expressed in the brain and nervous tissue and plays a key role in development, cell adhesion, and migration. Recent studies point to important roles for Sdc-3 in inflammatory disease, but the patterns of expression and significance of Sdc-3 in cancer remains unexplored. Here we show that Sdc-3 expression is upregulated on several cancer types, especially in solid tumors that are known to be hypoxic. The Cancer Genome Atlas program (TCGA) data demonstrated that Sdc-3 expression in the tumor microenvironment positively correlates with a hypoxia gene signature. To confirm a potential cause-effect, we performed experiments with tumor cell lines showing increased expression upon
MeSH term(s)	Cell Hypoxia/physiology ; Humans ; Syndecan-3/metabolism ; Tumor Microenvironment/physiology
Chemical Substances	SDC3 protein, human ; Syndecan-3
Language	English
Publishing date	2020-09-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.586977
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