Published December 10, 2025
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Immune cell senescence drives responsiveness to immunotherapy in melanoma.

Creators

  • 1. Department of Histology and Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece.
  • 2. National and Kapodistrian University of Athens
  • 3. Bioinformatics and Applied Genomics Unit, Hellenic Pasteur institute, Athens, 11521, Greece.
  • 4. Pasteur Institute
  • 5. Department of Biology, Flow Cytometry Unit, National and Kapodistrian University of Athens, Athens, 15701, Greece.
  • 6. Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD19SY, UK.
  • 7. Intelligencia Inc, New York, NY, 10014, USA.
  • 8. Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Tuebingen, 7207, Germany.
  • 9. First Department of Dermatology-Venereology, National and Kapodistrian University of Athens, Andreas Sygros Hospital, Athens, 161 21, Greece.
  • 10. Laboratory of Biology, Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece.
  • 11. Biomedical Research Foundation, Academy of Athens, Athens, 11527, Greece.
  • 12. Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, CH-9007, Switzerland.
  • 13. Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, 15341, Greece.
  • 14. University Research Institute of Maternal and Child Health and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece.
  • 15. UNESCO Chair On Adolescent Health Care, National and Kapodistrian University of Athens, Athens, 11527, Greece.
  • 16. University Research Institute, Choremeion-Aghia Sophia Children's Hospital, Athens, 11527, Greece.
  • 17. Department of Biotechnology, Laboratory of Genetics, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, 11855, Greece.
  • 18. Algorithms and Bioinformatics Group, Informatics Department, Faculty of Natural, Mathematical & Engineering Sciences, King's College, Strand Campus, London, WC2R 2LS, UK.
  • 19. Department of Histology and Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece. VGorgoulis001@dundee.ac.uk.
  • 20. Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD19SY, UK. VGorgoulis001@dundee.ac.uk.
  • 21. Intelligencia Inc, New York, NY, 10014, USA. VGorgoulis001@dundee.ac.uk.
  • 22. Biomedical Research Foundation, Academy of Athens, Athens, 11527, Greece. VGorgoulis001@dundee.ac.uk.
  • 23. Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M20 4GJ, UK. VGorgoulis001@dundee.ac.uk.
  • 24. University of Manchester

Description

Immunotherapy has significantly improved cancer treatment. However, it is not effective in all cancer patients, rendering the need to further delineate the differences among responders and non-responders at the molecular and cellular level. Unresponsiveness to immunotherapy has been attributed to dysfunctional immune cell states such as T-cell exhaustion and anergy, whereas the contribution of cellular senescence remains elusive. Herein, we have investigated the role of immune cell senescence in the response to checkpoint inhibitors in melanomas where these immunotherapies are applied as a first line treatment. Two senescence detecting complementary approaches were utilized in a case control study we conducted. First, we implemented a senescence molecular signature we developed, termed "SeneVick", retrospectively in a single cell RNA-seq dataset from melanoma patients who received immunotherapy. Prior to this analysis, the signature was extensively validated in a variety of cell/tissue contexts, senescence types and species. Second, cellular senescence was assessed via an established experimental algorithmic approach in circulating immune cells of an analogous melanoma clinical cohort. Melanoma patients who did not respond to immunotherapy exhibited increased cellular senescence in the CD8 + T-cell, CD4 + T-cell, B-cell (CD19 + /CD20 +) and NK cell compartments compared to responders. This phenomenon was independent of patients' clinical features (age, sex, melanoma type, stage) and not an outcome of immunotherapy, in contrast to conventional anti-cancer treatments. Interestingly, alterations of cell-to-cell interactions among the immune sub-populations in non-responders compared to responders were identified, supporting, along with cytotoxicity assays, that senescent immune cells display immunosuppressive properties driving defective immune responses and treatment failure. Overall, our findings provide evidence that cellular senescence within the immune cell compartment of the tumor micro-environment is a potent determinant of the response to immunotherapy and pave the way for strategies targeting it as promising approaches to improve the outcome of such interventions. © 2025. The Author(s).
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