A ganglioside-based immune checkpoint enables senescent cells to evade immunosurveillance during aging
Although senescent cells can be eliminated by the immune system, they tend to accumulate with age in various tissues. Here we show that senescent cells can evade immune clearance by natural killer (NK) cells by upregulating the expression of the disialylated ganglioside GD3 at their surface. The increased level of GD3 expression on senescent cells that naturally occurs upon aging in liver, lung, kidney or bones leads to a strong suppression of NK-cell-mediated immunosurveillance. In mice, we found that targeting GD3<sup>+</sup> senescent cells with anti-GD3 immunotherapy attenuated the development of experimentally induced or age-related lung and liver fibrosis and age-related bone remodeling. These results demonstrate that GD3 upregulation confers immune privilege to senescent cells. We propose that GD3 acts as a senescence immune checkpoint (SIC) that allows senescent cells to escape immunosurveillance and to trigger immune anergy during aging.
Authors
- Clément Philippe Delannoy (ORCID: https://orcid.org/0000-0002-2070-4000)
- Yann Guérardel (ORCID: https://orcid.org/0000-0003-4967-9512)
- Véronique M. Braud (ORCID: https://orcid.org/0000-0001-8213-3947)
- Manon Durandy (ORCID: https://orcid.org/0009-0006-3958-1609)
- Philippe Gual (ORCID: https://orcid.org/0000-0001-7393-8356)
- Bérengère Dadone‐Montaudié (ORCID: https://orcid.org/0000-0002-0339-4602)
- Marina Shkreli (ORCID: https://orcid.org/0000-0002-8615-1891)
- Christian Helms Jørgensen (ORCID: https://orcid.org/0000-0003-2521-7823)
- Maude Ardin
- Manon Bourinet
- Alexandre Ottaviani (ORCID: https://orcid.org/0000-0002-1564-0735)
- Delphine Benarroch-Popivker
- Charlène Iltis (ORCID: https://orcid.org/0000-0003-0637-1112)
- Jean‐Marc Brondello (ORCID: https://orcid.org/0000-0001-5991-3945)
- Yves‐Marie Pers (ORCID: https://orcid.org/0000-0001-5927-3773)
- Thierry Pourcher (ORCID: https://orcid.org/0000-0003-2839-4622)
- David Bernard (ORCID: https://orcid.org/0000-0002-1557-2074)
- Estelle Cosson (ORCID: https://orcid.org/0000-0001-9482-1755)
- Tynhinane Hamidouche
- Julien Guglielmi
- Laurence Bianchini (ORCID: https://orcid.org/0000-0002-2840-8900)
- Olivier Croce (ORCID: https://orcid.org/0000-0002-7342-3157)
- Marie‐Cécile Michallet (ORCID: https://orcid.org/0000-0001-5860-7460)
- Carmelo Luci (ORCID: https://orcid.org/0000-0001-9687-4164)
- Fabrice Allain (ORCID: https://orcid.org/0000-0002-4484-6302)
- Lyvia Moudombi
- Chloé C. Féral (ORCID: https://orcid.org/0000-0001-9756-2082)
- Didier F. Pisani (ORCID: https://orcid.org/0000-0001-5879-8527)
- Anthony Ferrari (ORCID: https://orcid.org/0009-0008-5386-5688)
- Iryna Moskalevska
- Julien Cherfils‐Vicini (ORCID: https://orcid.org/0000-0001-7813-1527)
- Antoine Debiesse
- Paul Hofman (ORCID: https://orcid.org/0000-0003-0431-9353)
- Christina Fissoun
- Gabriela Makulyte
- Éric Gilson (ORCID: https://orcid.org/0000-0001-5738-6723)
- Laetitia Seguin (ORCID: https://orcid.org/0000-0003-2950-4766)
- Lou C. Duret
- Sarah Kunz
- Ludovic Cervera
- Coline Eliott
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Université Côte d'Azur (FR)
- Université de Lille (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- CEA Grenoble (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Laboratoire de PhysioMédecine Moléculaire (FR)
- Centre Hospitalier Universitaire de Montpellier (FR)
- La Ligue Contre le Cancer (FR)
- Institute for Regenerative Medicine & Biotherapy (FR)
- Institut des Sciences du Vivant Frédéric Joliot (FR)
- Centre Léon Bérard (FR)
- CEA Cadarache (FR)
- Department of Virology (FR)
- Direction de la Recherche Fondamentale (FR)
- Unité de Glycobiologie Structurale et Fonctionnelle (FR)
- Centre Méditerranéen de Médecine Moléculaire (FR)
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Hôpital Pasteur (FR)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- Gifu University (JP)
Publication Details
- Journal
- Nature Aging
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1038/s43587-024-00776-z
- Citations
- 34
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 8.18
Funders
- Association pour la Recherche sur le Cancer
- Infrastructures en Biologie Santé et Agronomie
- Université de Lille
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Ministry of Natural Resources and Tourism
- Institut National Du Cancer
- Association Française pour l'Etude du Foie
- Direction Générale de l’offre de Soins
- Canceropôle Provence-Alpes-Côte d’Azur
- LabEx DEvweCAN
- National Institutes of Health
- Medical Research Council
- Inserm Transfert
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Common Fund