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Publication

Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells.

Cell reports | 2019

Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the PDCD1 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of CTLA4, LAG3, TIM3, TIGIT, and BTLA but not of the stimulatory co-receptors OX40, GITR, and 4-1BB mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy.

Pubmed ID: 30605689 RIS Download

Research resources used in this publication

HeLa (RRID:CVCL_0030) (cell line)

Additional research tools detected in this publication

Antibodies used in this publication

Associated grants

None

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This is a list of tools and resources that we have found mentioned in this publication.

ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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PRISM (tool)

RRID:SCR_005375

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.

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UTRdb/UTRsite (tool)

RRID:SCR_005868

UTRdb/UTRsite is a portal to other databases, including Nucleotide Sequence Databases, Protein Sequence Databases, other Sequence databanks, Untranslated Nucleotide Sequence Databases, Mitochondrial Databases, Mutation Databases, and others. The site also allows users to start long-term permanent projects or just to do quick searches, depending on the user''s needs.

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icy (tool)

RRID:SCR_010587

An open community platform for bioimage informatics providing the software resources to visualize, annotate and quantify bioimaging data. To bridge the gap between developers and users, it combines: a) an open-source image analysis software, offering a powerful and flexible environment for developers such as applied mathematicians to write algorithms fast and efficiently; b) a common set of tools to view and manipulate data, and a set of plugins to perform specific quantification or analysis on images; c) a community-based website centralizing all plugins and resources to facilitate their management and maximize their visibility towards users. Workspaces are virtual groups of plugins dedicated to a specific application or image processing domain. By downloading a workspace, ICY automatically installs all corresponding plugins. The workspaces are enabled, but the editing section is not ready yet. If you want to publish a plugin on this website, its code has to be GPL. Source code is available and provided in each application download.

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