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  1. Article ; Online: Intratumoral co-injection of NK cells and NKG2A-neutralizing monoclonal antibodies.

    Melero, Ignacio / Ochoa, Maria C / Molina, Carmen / Sanchez-Gregorio, Sandra / Garasa, Saray / Luri-Rey, Carlos / Hervas-Stubbs, Sandra / Casares, Noelia / Elizalde, Edurne / Gomis, Gabriel / Cirella, Assunta / Berraondo, Pedro / Teijeira, Alvaro / Alvarez, Maite

    EMBO molecular medicine

    2023  Volume 15, Issue 11, Page(s) e17804

    Abstract: NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa- ... ...

    Abstract NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa-1
    MeSH term(s) Mice ; Humans ; Animals ; Antibodies, Monoclonal/therapeutic use ; Histocompatibility Antigens Class I ; Killer Cells, Natural ; CD8-Positive T-Lymphocytes ; Neoplasms ; Tumor Microenvironment
    Chemical Substances Antibodies, Monoclonal ; Histocompatibility Antigens Class I
    Language English
    Publishing date 2023-10-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.202317804
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6784: Show issues Location:
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  2. Article ; Online: FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma.

    Conde, Enrique / Casares, Noelia / Mancheño, Uxua / Elizalde, Edurne / Vercher, Enric / Capozzi, Roberto / Santamaria, Eva / Rodriguez-Madoz, Juan R / Prosper, Felipe / Lasarte, Juan J / Lozano, Teresa / Hervas-Stubbs, Sandra

    Molecular therapy : the journal of the American Society of Gene Therapy

    2022  Volume 31, Issue 1, Page(s) 48–65

    Abstract: Regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive T cell therapy (ACT), we show ... ...

    Abstract Regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive T cell therapy (ACT), we show that FOXP3 overexpression in mature CD8 T cells improved their antitumor efficacy, favoring their tumor recruitment, proliferation, and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 T cells exhibited features of tissue-resident memory-like and effector T cells, but not suppressor activity. Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 T cells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism, and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 T cells exhibited an enhanced capacity for glucose and FA uptake as well as accumulation of intracellular lipids. Interestingly, Foxp3UP CD8 T cells compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energy demands. Importantly, their ability to couple glycolysis and OXPHOS allowed them to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role for FOXP3 in the adaptation of CD8 T cells to TME that may enhance their efficacy in ACT.
    MeSH term(s) Humans ; CD8-Positive T-Lymphocytes/immunology ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Glucose/metabolism ; Immunotherapy, Adoptive ; Melanoma/therapy ; Tumor Microenvironment
    Chemical Substances Forkhead Transcription Factors ; FOXP3 protein, human ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2022-08-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2022.08.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5640: Show issues Location:
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  3. Article ; Online: Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants.

    Conde, Enrique / Vercher, Enric / Soria-Castellano, Marta / Suarez-Olmos, Jesús / Mancheño, Uxua / Elizalde, Edurne / Rodriguez, M Luis / Glez-Vaz, Javier / Casares, Noelia / Rodríguez-García, Estefanía / Hommel, Mirja / González-Aseguinolaza, Gloria / Uranga-Murillo, Iratxe / Pardo, Julian / Alkorta, Gorka / Melero, Ignacio / Lasarte, Juan / Hervas-Stubbs, Sandra

    Journal for immunotherapy of cancer

    2021  Volume 9, Issue 11

    Abstract: Background: Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an ... ...

    Abstract Background: Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2'3'-cyclic GMP-AMP (2'3'-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism.
    Methods: Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2'3'-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed.
    Results: Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy. In this setting, the CART/STING-L combination, but not the monotherapy with CART cells or STING-L, restrained tumor progression and enhanced overall survival, showing abscopal effects on distal STING-L-non-treated tumors. Interestingly, a secondary immune response against non-chimeric antigen receptor-targeted Ags (epitope spreading), as determined by major histocompatibility complex-I-tetramer staining, was fostered and its intensity correlated with the efficacy of the combination. This was consistent with the oligoclonal expansion of host T cells, as revealed by in-depth T-cell receptor repertoire analysis. Moreover, only in the combination group did the activation of endogenous T cells translate into a systemic antitumor response. Importantly, the epitope spreading and the antitumor effects of the combination were fully dependent on host STING signaling and Batf3-dependent DCs, and were partially dependent on Perf release by CART cells. Interestingly, the efficacy of the CART/STING-L treatment also depended on STING signaling in CART cells.
    Conclusions: Our data show that 2'3'-cGAMP is a suitable adjuvant to combine with CART-cell therapy, allowing the induction of an endogenous T-cell response that prevents the outgrowth of Ag-loss tumor variants.
    MeSH term(s) Animals ; Epitopes/genetics ; Humans ; Immunotherapy/methods ; Immunotherapy, Adoptive/methods ; Male ; Mice ; Neoplasms/genetics ; Tumor Escape/genetics
    Chemical Substances Epitopes
    Language English
    Publishing date 2021-11-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2021-003351
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1

    Salas-Benito, Diego / Conde, Enrique / Tamayo-Uria, Ibon / Mancheño, Uxua / Elizalde, Edurne / Garcia-Ros, David / Aramendia, Jose M / Muruzabal, Juan C / Alcaide, Julia / Guillen-Grima, Francisco / Minguez, Jose A / Amores-Tirado, Jose / Gonzalez-Martin, Antonio / Sarobe, Pablo / Lasarte, Juan J / Ponz-Sarvise, Mariano / De Andrea, Carlos E / Hervas-Stubbs, Sandra

    British journal of cancer

    2021  Volume 124, Issue 6, Page(s) 1138–1149

    Abstract: Background: Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those ... ...

    Abstract Background: Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation.
    Methods: PD-1
    Results: Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1
    Conclusion: We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1
    MeSH term(s) Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphocytes, Tumor-Infiltrating/immunology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/immunology ; Ovarian Neoplasms/pathology ; Phenotype ; Prognosis ; Programmed Cell Death 1 Receptor/metabolism ; Retrospective Studies
    Chemical Substances Biomarkers, Tumor ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2021-01-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/s41416-020-01218-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  5. Article ; Online: Expansion of Tumor-Infiltrating CD8

    Fernandez-Poma, Sarita M / Salas-Benito, Diego / Lozano, Teresa / Casares, Noelia / Riezu-Boj, Jose-Ignacio / Mancheño, Uxua / Elizalde, Edurne / Alignani, Diego / Zubeldia, Natalia / Otano, Itziar / Conde, Enrique / Sarobe, Pablo / Lasarte, Juan Jose / Hervas-Stubbs, Sandra

    Cancer research

    2017  Volume 77, Issue 13, Page(s) 3672–3684

    Abstract: Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD- ... ...

    Abstract Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Humans ; Immunotherapy, Adoptive/methods ; Lymphocytes, Tumor-Infiltrating/immunology ; Melanoma, Experimental/immunology ; Melanoma, Experimental/therapy ; Mice ; Mice, Inbred C57BL ; Programmed Cell Death 1 Receptor/biosynthesis ; Programmed Cell Death 1 Receptor/immunology
    Chemical Substances Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2017-07-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-17-0236
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.135/5: Show issues Location:
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  6. Article: Hepatitis C virus infection of primary tupaia hepatocytes leads to selection of quasispecies variants, induction of interferon-stimulated genes and NF-kappaB nuclear translocation.

    Guitart, Anunciata / Riezu-Boj, José-Ignacio / Elizalde, Edurne / Larrea, Esther / Berasain, Carmen / Aldabe, Rafael / Civeira, Maria Pilar / Prieto, Jesús

    The Journal of general virology

    2005  Volume 86, Issue Pt 11, Page(s) 3065–3074

    Abstract: Systems for in vitro culture of Hepatitis C virus (HCV) are essential tools to analyse virus-cell interactions and to investigate relevant pathophysiological aspects of HCV infection. Although the HCV replicon methodology has increased our understanding ... ...

    Abstract Systems for in vitro culture of Hepatitis C virus (HCV) are essential tools to analyse virus-cell interactions and to investigate relevant pathophysiological aspects of HCV infection. Although the HCV replicon methodology has increased our understanding of HCV biology, this system does not reproduce the natural infection. Recently, tupaia (Tupaia belangeri chinensis) hepatocytes have been utilized for in vitro culture of HCV. In the present work, primary tupaia hepatocytes infected in vitro with HCV were used to analyse the evolution of HCV quasispecies in infected cells and the ability of the virus to influence antiviral and proinflammatory responses in cells sustaining virus replication. The results confirmed the potential of tupaia hepatocytes as a model for HCV infection, although this system is limited by rapid loss of differentiated cell phenotype in culture. These findings revealed an extraordinary plasticity of HCV quasispecies, which underwent rapid evolution to tupaia-tropic variants as early as 24 h after infection. It was also shown that HCV could activate interferon-sensitive genes, albeit modestly in comparison with other viruses such as Semliki Forest virus. Importantly, HCV activated NF-kappaB in primary hepatocytes and upregulated NF-kappaB-responsive genes including the chemokines MCP-1 and CXCL2 (MIP-2). This effect may play a role in induction of the hepatic inflammatory reaction in vivo. In summary, HCV quasispecies adapt rapidly to the specific biology of the host and HCV stimulates a blunted interferon response while inducing a proinflammatory phenotype in the infected cell.
    MeSH term(s) Active Transport, Cell Nucleus ; Animals ; Gene Expression Regulation/drug effects ; Hepacivirus/classification ; Hepacivirus/genetics ; Hepacivirus/physiology ; Hepatitis C/genetics ; Hepatitis C/metabolism ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Hepatocytes/virology ; Humans ; Interferons/pharmacology ; Molecular Sequence Data ; NF-kappa B/metabolism ; Tupaia/virology ; Viral Envelope Proteins/metabolism
    Chemical Substances NF-kappa B ; Viral Envelope Proteins ; Interferons (9008-11-1)
    Language English
    Publishing date 2005-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/vir.0.81273-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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