Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens

Autor: Dolor Renko, Romain Darrigrand, Marine Rouillon, Mouad Alami, Mathilde Boulpicante, Julien Marcoux, Michael Ghosh, Camille Garcia, Alison Pierson, David Bouyssié, Sébastien Apcher, Emmanuelle Mouton-Barbosa
Přispěvatelé: Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), University of Tübingen
Rok vydání: 2021
Předmět:
0301 basic medicine
Fibrosarcoma
T-Lymphocytes
[SDV]Life Sciences [q-bio]
medicine.medical_treatment
Medicine (miscellaneous)
Adaptive Immunity
Lymphocyte Activation
Epitope
Mice
0302 clinical medicine
Cancer immunotherapy
Tumor Microenvironment
Biology (General)
Cancer
biology
Drug discovery
Chemistry
Tumor Burden
3. Good health
030220 oncology & carcinogenesis
Tumour immunology
Female
General Agricultural and Biological Sciences
Cell activation
Spliceosome
QH301-705.5
Immunology
Antigen presentation
Major histocompatibility complex
Cancer Vaccines
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Lymphocytes
Tumor-Infiltrating
Antigen
Antigens
Neoplasm
Cell Line
Tumor
MHC class I
medicine
Animals
Biflavonoids
Cell Proliferation
Histocompatibility Antigens Class I
Antineoplastic Agents
Phytogenic
Mice
Inbred C57BL
030104 developmental biology
biology.protein
Cancer research
Imidazoline Receptors
Zdroj: Communications Biology
Communications Biology, Nature Publishing Group, 2021, 4 (1), ⟨10.1038/s42003-021-01801-2⟩
Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021)
ISSN: 2399-3642
DOI: 10.1038/s42003-021-01801-2
Popis: The success of cancer immunotherapy relies on the induction of an immunoprotective response targeting tumor antigens (TAs) presented on MHC-I molecules. We demonstrated that the splicing inhibitor isoginkgetin and its water-soluble and non-toxic derivative IP2 act at the production stage of the pioneer translation products (PTPs). We showed that IP2 increases PTP-derived antigen presentation in cancer cells in vitro and impairs tumor growth in vivo. IP2 action is long-lasting and dependent on the CD8+ T cell response against TAs. We observed that the antigen repertoire displayed on MHC-I molecules at the surface of MCA205 fibrosarcoma is modified upon treatment with IP2. In particular, IP2 enhances the presentation of an exon-derived epitope from the tumor suppressor nischarin. The combination of IP2 with a peptide vaccine targeting the nischarin-derived epitope showed a synergistic antitumor effect in vivo. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies.
Darrigrand, Pierson et al. study the effect of mRNA splicing inhibitors on the generation of the MHC class I ligands. They developed a derivative of the spliceosome inhibitor isoginkgetin which is less toxic and more effective at enhancing antigen presentation and CD8+ T cell activation and showed greater antitumour activity in vivo. These findings identify the spliceosome as a druggable target for the development of epitope-based immunotherapies.
Databáze: OpenAIRE
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