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  1. Article ; Online: Tertiary lymphoid structures in cancer.

    Schumacher, Ton N / Thommen, Daniela S

    Science (New York, N.Y.)

    2022  Volume 375, Issue 6576, Page(s) eabf9419

    Abstract: Ectopic lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are formed in numerous cancer types, and, with few exceptions, their presence is associated with superior prognosis and response to immunotherapy. In spite of their presumed ... ...

    Abstract Ectopic lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are formed in numerous cancer types, and, with few exceptions, their presence is associated with superior prognosis and response to immunotherapy. In spite of their presumed importance, the triggers that lead to TLS formation in cancer tissue and the contribution of these structures to intratumoral immune responses remain incompletely understood. Here, we discuss the present knowledge on TLSs in cancer, focusing on (i) the drivers of TLS formation, (ii) the function and contribution of TLSs to the antitumor immune response, and (iii) the potential of TLSs as therapeutic targets in human cancers.
    MeSH term(s) Adaptive Immunity ; Animals ; Humans ; Immune Checkpoint Inhibitors ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Prognosis ; Tertiary Lymphoid Structures/immunology ; Tertiary Lymphoid Structures/pathology
    Chemical Substances Immune Checkpoint Inhibitors
    Language English
    Publishing date 2022-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abf9419
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Next generation T cell therapies for solid cancers.

    Haanen, John B / Schumacher, Ton N

    Med (New York, N.Y.)

    2022  Volume 3, Issue 10, Page(s) 645–647

    Abstract: Tumor-infiltrating lymphocytes show consistent clinical benefit in metastatic melanoma, but they are a poorly defined product with variable antitumor activity. In this issue, Palmer et al. ...

    Abstract Tumor-infiltrating lymphocytes show consistent clinical benefit in metastatic melanoma, but they are a poorly defined product with variable antitumor activity. In this issue, Palmer et al.
    MeSH term(s) Humans ; Lymphocyte Activation ; Lymphocytes, Tumor-Infiltrating ; Melanoma/therapy ; T-Lymphocytes/pathology
    Language English
    Publishing date 2022-10-13
    Publishing country United States
    Document type Journal Article ; Comment
    ISSN 2666-6340
    ISSN (online) 2666-6340
    DOI 10.1016/j.medj.2022.09.008
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  3. Article ; Online: Multimodular Optimization of Chemically Regulated T Cell Switches Demonstrates Flexible and Interchangeable Nature of Immune Cell Signaling Domains.

    Sahillioglu, Ali Can / Schumacher, Ton N

    Human gene therapy

    2021  Volume 32, Issue 19-20, Page(s) 1029–1043

    Abstract: Immune cell-based therapies can induce potent antitumor effects but are also often associated with severe toxicities. We previously developed a PD-1-based small molecule-regulated reversible T cell activation switch to control the activity of cellular ... ...

    Abstract Immune cell-based therapies can induce potent antitumor effects but are also often associated with severe toxicities. We previously developed a PD-1-based small molecule-regulated reversible T cell activation switch to control the activity of cellular immunotherapy products. This chemically regulated and SH2-delivered-inhibitory tail (CRASH-IT) switch relies on the noncovalent interaction of switch SH2 domains with phosphorylated ITAM motifs in either chimeric antigen receptors or T cell receptors. After this interaction, the immunoreceptor tyrosine-based inhibition motif/switch motif (ITIM/ITSM) containing PD-1 domain present in the CRASH-IT switch induces robust inhibition of T cell signaling, and CRASH-IT-mediated suppression of T cell activity can be reversed by small molecule-induced switch proteolysis. With the aim to develop improved second-generation switch systems, we here analyze the possibility space of both the immune cell receptor docking and inhibitory signaling domains that allow control over T cell activity. Importantly, these analyses demonstrate that the inhibitory domains that most potently suppress antigen receptor signaling in primary human T cells are not derived from inhibitory receptors, such as PD-1 and BTLA, that are endogenously expressed in T cells, but include ITIM/ITSM containing inhibitory domains derived from receptors present in myeloid cells. In addition, we demonstrate that physical proximity of the inhibitory domain to the antigen receptor is crucial to efficiently suppress T cell activation, as only switch designs that employ SH2 domains directly interacting with ITAM motifs in antigen receptors efficiently and reversibly inhibit T cell functionality. These data demonstrate the flexible and interchangeable nature of immune cell signaling domains, and inform the design of a synthetic proximity-based switch system with a superior dynamic range.
    MeSH term(s) Humans ; Phosphorylation ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Immunologic/metabolism ; Signal Transduction ; T-Lymphocytes/metabolism ; src Homology Domains
    Chemical Substances Receptors, Antigen, T-Cell ; Receptors, Immunologic
    Language English
    Publishing date 2021-10-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1028152-6
    ISSN 1557-7422 ; 1043-0342
    ISSN (online) 1557-7422
    ISSN 1043-0342
    DOI 10.1089/hum.2021.148
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    Zs.A 2988: Show issues Location:
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  4. Article ; Online: Safety switches for adoptive cell therapy.

    Sahillioglu, Ali Can / Schumacher, Ton N

    Current opinion in immunology

    2021  Volume 74, Page(s) 190–198

    Abstract: Adoptive transfer of allogeneic and genetically modified T cells, such as CAR-T and TCR-T cells, can induce profound immune reactivity against cancer tissue. At the same time, these therapies are associated with severe off-target and on-target toxicities. ...

    Abstract Adoptive transfer of allogeneic and genetically modified T cells, such as CAR-T and TCR-T cells, can induce profound immune reactivity against cancer tissue. At the same time, these therapies are associated with severe off-target and on-target toxicities. For this reason, the development of genetic safety switches that can be used to control the activity of T cells in vivo has become an active field of research. With the spectrum of technologies developed, reversible control of cell products either by supply or removal of small molecules, by supply of protein-based regulators, or by physical stimuli such as light, ultrasound or heat, has become feasible. In this review, we describe the mechanistic classes of genetic safety switches, such as transcription-based or protein-based control of antigen receptors, split receptors, small molecule responsive antibodies, as well as universal remote controls, and discuss their advantages and limitations.
    MeSH term(s) Cell- and Tissue-Based Therapy ; Humans ; Immunotherapy, Adoptive/adverse effects ; Neoplasms/therapy ; Receptors, Antigen ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes
    Chemical Substances Receptors, Antigen ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2021-08-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1035767-1
    ISSN 1879-0372 ; 0952-7915
    ISSN (online) 1879-0372
    ISSN 0952-7915
    DOI 10.1016/j.coi.2021.07.002
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  5. Article ; Online: The Effect of Race/Ethnicity and MED12 Mutation on the Expression of Long Non-Coding RNAs in Uterine Leiomyoma and Myometrium.

    Chuang, Tsai-Der / Ton, Nhu / Rysling, Shawn / Boos, Drake / Khorram, Omid

    International journal of molecular sciences

    2024  Volume 25, Issue 2

    Abstract: The objective of this study was to elucidate the expression of long non-coding RNA (lncRNA) in leiomyomas (Lyo) and paired myometrium (Myo) and explore the impact of race and MED12 mutation. Fold change analysis (Lyo/paired Myo) indicated the expression ... ...

    Abstract The objective of this study was to elucidate the expression of long non-coding RNA (lncRNA) in leiomyomas (Lyo) and paired myometrium (Myo) and explore the impact of race and MED12 mutation. Fold change analysis (Lyo/paired Myo) indicated the expression of 63 lncRNAs was significantly altered in the mutated group but not in the non-mutated Lyo. Additionally, 65 lncRNAs exhibited an over 1.5-fold change in the Black but not the White group. Fifteen differentially expressed lncRNAs identified with next-generation sequencing underwent qRT-PCR confirmation. Compared with Myo, the expression of
    MeSH term(s) Female ; Humans ; Ethnicity ; Leiomyoma/genetics ; Leiomyoma/metabolism ; Mediator Complex/genetics ; Mediator Complex/metabolism ; Mutation ; Myometrium/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Transcription Factors/metabolism ; Uterine Neoplasms/genetics ; Uterine Neoplasms/metabolism
    Chemical Substances MED12 protein, human ; Mediator Complex ; RNA, Long Noncoding ; Transcription Factors
    Language English
    Publishing date 2024-01-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms25021307
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  6. Article ; Online: Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma.

    Klobuch, Sebastian / Seijkens, Tom T P / Schumacher, Ton N / Haanen, John B A G

    Nature reviews. Clinical oncology

    2024  Volume 21, Issue 3, Page(s) 173–184

    Abstract: Immunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these breakthroughs, the 5-year survival rate of patients with advanced- ... ...

    Abstract Immunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these breakthroughs, the 5-year survival rate of patients with advanced-stage melanoma is at most 50%, emphasizing the need for additional therapeutic strategies. Adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) is a therapeutic modality that has, in the past few years, demonstrated long-term clinical benefit in phase II/III trials involving patients with advanced-stage melanoma, including those with disease progression on ICIs and/or BRAF/MEK inhibitors. In this Review, we summarize the current status of TIL therapies for patients with advanced-stage melanoma, including potential upcoming marketing authorization, the characteristics of TIL therapy products, as well as future strategies that are expected to increase the efficacy of this promising cellular immunotherapy.
    MeSH term(s) Humans ; Melanoma/therapy ; Immunotherapy, Adoptive ; Lymphocytes, Tumor-Infiltrating ; Proto-Oncogene Proteins B-raf ; Mitogen-Activated Protein Kinase Kinases
    Chemical Substances Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
    Language English
    Publishing date 2024-01-08
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2491410-1
    ISSN 1759-4782 ; 1759-4774
    ISSN (online) 1759-4782
    ISSN 1759-4774
    DOI 10.1038/s41571-023-00848-w
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    Zs.A 6029: Show issues Location:
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  7. Article ; Online: When Cancer Cells Become the Enablers of an Antitumor Immune Response.

    Ribas, Antoni / Haining, W Nicholas / Schumacher, Ton N M

    Cancer discovery

    2022  Volume 12, Issue 10, Page(s) 2244–2248

    Abstract: Tumor-specific cytotoxic T cells unleashed by the blockade of immune checkpoints have to overcome a hostile tumor microenvironment (TME). They start from very small numbers of T cells with tumor antigen specificity and, despite expansion, likely remain ... ...

    Abstract Tumor-specific cytotoxic T cells unleashed by the blockade of immune checkpoints have to overcome a hostile tumor microenvironment (TME). They start from very small numbers of T cells with tumor antigen specificity and, despite expansion, likely remain at a numerical disadvantage to the tumor cells they target. To overcome these obstacles, we propose that T cells need to change the TME to make it permissive for their antitumor effects by altering the phenotype of cells beyond the cancer cells they are in physical contact with. In this process, IFNγ secreted by tumor-specific T cells plays a critical role, as it changes the expression of hundreds of genes in cancer cells and other immune cells in the TME up to 40 layers of cells away from their location, effectively turning these cells into enablers of the antitumor immune response. In this perspective, we postulate that the clinical activity of cancer immunotherapy with immune-checkpoint blocking antibodies and adoptively transferred T cells requires that cancer cells facilitate the antitumor immune response. IFNγ effectively changes the balance of power in the TME to enable the antitumor activity of tumor antigen-specific cytotoxic T cells.
    MeSH term(s) Antibodies, Blocking ; Antigens, Neoplasm ; Humans ; Immunity ; Immunotherapy ; Neoplasms/genetics ; Neoplasms/therapy ; Tumor Microenvironment
    Chemical Substances Antibodies, Blocking ; Antigens, Neoplasm
    Language English
    Publishing date 2022-09-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-22-0706
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Formation of Tissue-Resident CD8

    Dijkgraaf, Feline E / Kok, Lianne / Schumacher, Ton N M

    Cold Spring Harbor perspectives in biology

    2021  Volume 13, Issue 8

    Abstract: Resident memory ... ...

    Abstract Resident memory CD8
    MeSH term(s) Animals ; CD8-Positive T-Lymphocytes/physiology ; Cell Differentiation ; Humans ; Immunologic Memory ; Memory T Cells/physiology
    Language English
    Publishing date 2021-08-02
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1943-0264
    ISSN (online) 1943-0264
    DOI 10.1101/cshperspect.a038117
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  9. Article ; Online: An atlas of intratumoral T cells.

    van der Leun, Anne M / Schumacher, Ton N

    Science (New York, N.Y.)

    2021  Volume 374, Issue 6574, Page(s) 1446–1447

    Abstract: Intratumoral T cell composition is relevant for disease outcome across tumor types. ...

    Abstract Intratumoral T cell composition is relevant for disease outcome across tumor types.
    MeSH term(s) T-Lymphocytes
    Language English
    Publishing date 2021-12-16
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abm9244
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  10. Article ; Online: The precursors of CD8

    Kok, Lianne / Masopust, David / Schumacher, Ton N

    Nature reviews. Immunology

    2021  Volume 22, Issue 5, Page(s) 283–293

    Abstract: ... ...

    Abstract CD8
    MeSH term(s) CD8-Positive T-Lymphocytes ; Cell Differentiation ; Cell Lineage ; Humans ; Immunologic Memory ; Memory T Cells
    Language English
    Publishing date 2021-09-03
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-021-00590-3
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