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  1. Article: Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies.

    Yélamos, José / Moreno-Lama, Lucia / Jimeno, Jaime / Ali, Syed O

    Cancers

    2020  Volume 12, Issue 2

    Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which post-translationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein ... ...

    Abstract Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 are enzymes which post-translationally modify proteins through poly(ADP-ribosyl)ation (PARylation)-the transfer of ADP-ribose chains onto amino acid residues-with a resultant modulation of protein function. Many targets of PARP-1/2-dependent PARylation are involved in the DNA damage response and hence, the loss of these proteins disrupts a wide range of biological processes, from DNA repair and epigenetics to telomere and centromere regulation. The central role of these PARPs in DNA metabolism in cancer cells has led to the development of PARP inhibitors as new cancer therapeutics, both as adjuvant treatment potentiating chemo-, radio-, and immuno-therapies and as monotherapy exploiting cancer-specific defects in DNA repair. However, a cancer is not just made up of cancer cells and the tumor microenvironment also includes multiple other cell types, particularly stromal and immune cells. Interactions between these cells-cancerous and non-cancerous-are known to either favor or limit tumorigenesis. In recent years, an important role of PARP-1 and PARP-2 has been demonstrated in different aspects of the immune response, modulating both the innate and adaptive immune system. It is now emerging that PARP-1 and PARP-2 may not only impact cancer cell biology, but also modulate the anti-tumor immune response. Understanding the immunomodulatory roles of PARP-1 and PARP-2 may provide invaluable clues to the rational development of more selective PARP-centered therapies which target both the cancer and its microenvironment.
    Language English
    Publishing date 2020-02-08
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers12020392
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Engineered cell-based therapies in ex vivo ready-made CellDex capsules have therapeutic efficacy in solid tumors.

    van Schaik, Thijs A / Moreno-Lama, Lucia / Aligholipour Farzani, Touraj / Wang, Mian / Chen, Kok-Siong / Li, Wanlu / Cai, Ling / Zhang, Yu Shrike / Shah, Khalid

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2023  Volume 162, Page(s) 114665

    Abstract: Encapsulated cell-based therapies for solid tumors have shown promising results in pre-clinical settings. However, the inability to culture encapsulated therapeutic cells prior to their transplantation has limited their translation into clinical settings. ...

    Abstract Encapsulated cell-based therapies for solid tumors have shown promising results in pre-clinical settings. However, the inability to culture encapsulated therapeutic cells prior to their transplantation has limited their translation into clinical settings. In this study, we created a wide variety of engineered therapeutic cells (ThC) loaded in micropore-forming gelatin methacryloyl (GelMA) hydrogel (CellDex) capsules that can be cultured in vitro prior to their transplantation in surgically debulked solid tumors. We show that both allogeneic and autologous engineered cells, such as stem cells (SCs), macrophages, NK cells, and T cells, proliferate within CellDex capsules and migrate out of the gel in vitro and in vivo. Furthermore, tumor cell specific therapeutic proteins and oncolytic viruses released from CellDex capsules retain and prolong their anti-tumor effects. In vivo, ThCs in pre-manufactured Celldex capsules persist long-term and track tumor cells. Moreover, chimeric antigen receptor (CAR) T cell bearing CellDex (T-CellDex) and human SC releasing therapeutic proteins (hSC-CellDex) capsules show therapeutic efficacy in metastatic and primary brain tumor resection models that mimic standard of care of tumor resection in patients. Overall, this unique approach of pre-manufactured micropore-forming CellDex capsules offers an effective off-the-shelf clinically viable strategy to treat solid tumors locally.
    MeSH term(s) Humans ; Neoplasms/pathology ; Receptors, Chimeric Antigen/metabolism ; Killer Cells, Natural ; T-Lymphocytes ; Cell- and Tissue-Based Therapy ; Immunotherapy, Adoptive/methods
    Chemical Substances Receptors, Chimeric Antigen
    Language English
    Publishing date 2023-04-14
    Publishing country France
    Document type Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2023.114665
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Coordinated signals from the DNA repair enzymes PARP-1 and PARP-2 promotes B-cell development and function.

    Galindo-Campos, Miguel A / Bedora-Faure, Marie / Farrés, Jordi / Lescale, Chloé / Moreno-Lama, Lucia / Martínez, Carlos / Martín-Caballero, Juan / Ampurdanés, Coral / Aparicio, Pedro / Dantzer, Françoise / Cerutti, Andrea / Deriano, Ludovic / Yélamos, José

    Cell death and differentiation

    2019  Volume 26, Issue 12, Page(s) 2667–2681

    Abstract: Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β- ... ...

    Abstract Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 regulate the function of various DNA-interacting proteins by transferring ADP-ribose emerging from catalytic cleavage of cellular β-NAD
    MeSH term(s) Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/metabolism ; DNA Repair ; Gene Rearrangement ; Genes, Immunoglobulin ; Humans ; Mice ; Mice, Knockout ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly(ADP-ribose) Polymerases/deficiency ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism
    Chemical Substances Parp1 protein, mouse (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Parp2 protein, mouse (EC 2.4.2.30.)
    Language English
    Publishing date 2019-04-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-019-0326-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Coordinated signals from PARP-1 and PARP-2 are required to establish a proper T cell immune response to breast tumors in mice.

    Moreno-Lama, Lucia / Galindo-Campos, Miguel A / Martínez, Carlos / Comerma, Laura / Vazquez, Ivonne / Vernet-Tomas, María / Ampurdanés, Coral / Lutfi, Nura / Martin-Caballero, Juan / Dantzer, Françoise / Quintela-Fandino, Miguel / Ali, Syed O / Jimeno, Jaime / Yélamos, José

    Oncogene

    2020  Volume 39, Issue 13, Page(s) 2835–2843

    Abstract: Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, ...

    Abstract Poly(ADP-ribose)-polymerase (PARP)-1 and PARP-2 play an essential role in the DNA damage response. Based on this effect of PARP in the tumor cell itself, PARP inhibitors have emerged as new therapeutic tools both approved and in clinical trials. However, the interactome of multiple other cell types, particularly T cells, within the tumor microenvironment are known to either favor or limit tumorigenesis. Here, we bypassed the embryonic lethality of dually PARP-1/PARP-2-deficient mice by using a PARP-1-deficient mouse with a Cd4-promoter-driven deletion of PARP-2 in T cells to investigate the understudied role of these PARPs in the modulation of T cell responses against AT-3-induced breast tumors. We found that dual PARP-1/PARP-2-deficiency in T cells promotes tumor growth while single deficiency of each protein limited tumor progression. Analysis of tumor-infiltrating cells in dual PARP-1/PARP-2-deficiency host-mice revealed a global change in immunological profile and impaired recruitment and activation of T cells. Conversely, single PARP-1 and PARP-2-deficiency tends to produce an environment with an active and partially upregulated immune response. Our findings pinpoint opposite effects of single and dual PARP-1 and PARP-2-deficiency in modulating the antitumor response with an impact on tumor progression, and will have implications for the development of more selective PARP-centered therapies.
    MeSH term(s) Animals ; Carcinogenesis/drug effects ; Carcinogenesis/immunology ; Cell Line, Tumor/transplantation ; Disease Progression ; Female ; Humans ; Immunity, Cellular ; Mammary Glands, Human/immunology ; Mammary Glands, Human/pathology ; Mammary Neoplasms, Experimental/drug therapy ; Mammary Neoplasms, Experimental/immunology ; Mammary Neoplasms, Experimental/pathology ; Mice ; Mice, Knockout ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Tumor Escape ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors ; Parp1 protein, mouse (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Parp2 protein, mouse (EC 2.4.2.30.)
    Language English
    Publishing date 2020-01-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-020-1175-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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